US8410136B2 - Methods for treatment of hepatocellular carcinoma using 3-(4-amino-1-OXO-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione - Google Patents
Methods for treatment of hepatocellular carcinoma using 3-(4-amino-1-OXO-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione Download PDFInfo
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- US8410136B2 US8410136B2 US12/755,904 US75590410A US8410136B2 US 8410136 B2 US8410136 B2 US 8410136B2 US 75590410 A US75590410 A US 75590410A US 8410136 B2 US8410136 B2 US 8410136B2
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Definitions
- This invention relates to methods of treating, preventing and/or managing specific cancers, and other diseases including, but not limited to, those associated with, or characterized by, undesired angiogenesis, by the administration of one or more immunomodulatory compounds alone or in combination with other therapeutics.
- the invention encompasses the use of specific combinations, or “cocktails”, of drugs and other therapy, e.g., radiation to treat these specific cancers, including those refractory to conventional therapy.
- the invention also relates to pharmaceutical compositions and dosing regimens.
- Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis).
- Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia.
- the neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host's immune surveillance.
- cancers There is an enormous variety of cancers which are described in detail in the medical literature. Examples includes cancer of the lung, colon, rectum, prostate, breast, brain, and intestine. The incidence of cancer continues to climb as the general population ages, as new cancers develop, and as susceptible populations (e.g., people infected with AIDS or excessively exposed to sunlight) grow. A tremendous demand therefore exists for new methods and compositions that can be used to treat patients with cancer.
- angiogenesis a process known as angiogenesis.
- cytokines include acidic and basic fibroblastic growth factor (a,b-FGF), angiogenin, vascular endothelial growth factor (VEGF), and TNF- ⁇ .
- a,b-FGF acidic and basic fibroblastic growth factor
- VEGF vascular endothelial growth factor
- TNF- ⁇ tumor cell
- tumor cells can release angiogenic peptides through the production of proteases and the subsequent breakdown of the extracellular matrix where some cytokines are stored (e.g., b-FGF).
- Angiogenesis can also be induced indirectly through the recruitment of inflammatory cells (particularly macrophages) and their subsequent release of angiogenic cytokines (e.g., TNF- ⁇ , bFGF).
- angiogenesis A variety of other diseases and disorders are also associated with, or characterized by, undesired angiogenesis.
- enhanced or unregulated angiogenesis has been implicated in a number of diseases and medical conditions including, but not limited to, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, rubeosis (neovascularization of the angle), viral diseases, genetic diseases, inflammatory diseases, allergic diseases, and autoimmune diseases.
- diseases and conditions include, but are not limited to: diabetic retinopathy; retinopathy of prematurity; corneal graft rejection; neovascular glaucoma; retrolental fibroplasia; and proliferative vitreoretinopathy.
- compounds that can control angiogenesis or inhibit the production of certain cytokines, including TNF- ⁇ may be useful in the treatment and prevention of various diseases and conditions.
- hormonal therapy can be effective, it is often used to prevent or delay recurrence of cancer after other treatments have removed the majority of cancer cells.
- Biological therapies and immunotherapies are limited in number and may produce side effects such as rashes or swellings, flu-like symptoms, including fever, chills and fatigue, digestive tract problems or allergic reactions.
- chemotherapeutic agents available for treatment of cancer.
- a majority of cancer chemotherapeutics act by inhibiting DNA synthesis, either directly, or indirectly by inhibiting the biosynthesis of deoxyribonucleotide triphosphate precursors, to prevent DNA replication and concomitant cell division.
- chemotherapeutic agents Despite availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks. Stockdale, Medicine , vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant, and often dangerous side effects including severe nausea, bone marrow depression, and immunosuppression. Additionally, even with administration of combinations of chemotherapeutic agents, many tumor cells are resistant or develop resistance to the chemotherapeutic agents. In fact, those cells resistant to the particular chemotherapeutic agents used in the treatment protocol often prove to be resistant to other drugs, even if those agents act by different mechanism from those of the drugs used in the specific treatment. This phenomenon is referred to as pleiotropic drug or multidrug resistance. Because of the drug resistance, many cancers prove refractory to standard chemotherapeutic treatment protocols.
- IMiDTMs include, but are not limited to, the substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles described in U.S. Pat. Nos. 6,281,230 and 6,316,471, both to G. W. Muller, et al.
- This invention encompasses methods of treating and preventing certain types of cancer, including primary and metastatic cancer, as well as cancers that are refractory or resistant to conventional chemotherapy.
- the methods comprise administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
- the invention also encompasses methods of managing certain cancers (e.g., preventing or prolonging their recurrence, or lengthening the time of remission) which comprise administering to a patient in need of such management a prophylactically effective amount of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
- an immunomodulatory compound is administered in combination with a therapy conventionally used to treat, prevent or manage cancer.
- a therapy conventionally used to treat, prevent or manage cancer examples include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy.
- This invention also encompasses methods of treating, managing or preventing diseases and disorders other than cancer that are associated with, or characterized by, undesired angiogenesis, which comprise administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
- an immunomodulatory compound is administered in combination with a therapy conventionally used to treat, prevent or manage diseases or disorders associated with, or characterized by, undesired angiogenesis.
- a therapy conventionally used to treat, prevent or manage diseases or disorders associated with, or characterized by, undesired angiogenesis.
- conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy.
- compositions single unit dosage forms, dosing regimens and kits which comprise an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second, or additional, active agent.
- Second active agents include specific combinations, or “cocktails”, of drugs.
- FIG. 1 shows a comparison of the effects of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (RevimidTM) and thalidomide in inhibiting the proliferation of multiple myeloma (MM) cell lines in an in vitro study.
- the uptake of [ 3 H]-thymidine by different MM cell lines was measured as an indicator of the cell proliferation.
- a first embodiment of the invention encompasses methods of treating, managing, or preventing cancer which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
- the immunomodulatory compound is administered in combination with another drug (“second active agent”) or method of treating, managing, or preventing cancer.
- Second active agents include small molecules and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells.
- Methods, or therapies, that can be used in combination with the administration of the immunomodulatory compound include, but are not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy, and other non-drug based therapies presently used to treat, prevent or manage cancer.
- Another embodiment of the invention encompasses methods of treating, managing or preventing diseases and disorders other than cancer that are characterized by undesired angiogenesis. These methods comprise the administration of a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
- diseases and disorders associated with, or characterized by, undesired angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, and rubeosis (neovascularization of the angle).
- the immunomodulatory compound is administer in combination with a second active agent or method of treating, managing, or preventing the disease or condition.
- Second active agents include small molecules and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells.
- Methods, or therapies, that can be used in combination with the administration of the immunomodulatory compound include, but are not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy, and other non-drug based therapies presently used to treat, prevent or manage disease and conditions associated with, or characterized by, undesired angiogenesis.
- compositions e.g., single unit dosage forms
- pharmaceutical compositions comprise an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active agent.
- Compounds used in the invention include immunomodulatory compounds that are racemic, stereomerically enriched or stereomerically pure, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof.
- Preferred compounds used in the invention are small organic molecules having a molecular weight less than about 1,000 g/mol, and are not proteins, peptides, oligonucleotides, oligosaccharides or other macromolecules.
- immunomodulatory compounds and “IMiDsTM” (Celgene Corporation) encompasses small organic molecules that markedly inhibit TNF- ⁇ , LPS induced monocyte IL1 ⁇ and IL12, and partially inhibit IL6 production. Specific immunomodulatory compounds are discussed below.
- TNF- ⁇ is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. TNF- ⁇ is responsible for a diverse range of signaling events within cells. TNF- ⁇ may play a pathological role in cancer. Without being limited by theory, one of the biological effects exerted by the immunomodulatory compounds of the invention is the reduction of synthesis of TNF- ⁇ . Immunomodulatory compounds of the invention enhance the degradation of TNF- ⁇ mRNA.
- immunomodulatory compounds used in the invention may also be potent co-stimulators of T cells and increase cell proliferation dramatically in a dose dependent manner. Immunomodulatory compounds of the invention may also have a greater co-stimulatory effect on the CD8+ T cell subset than on the CD4+ T cell subset. In addition, the compounds preferably have anti-inflammatory properties, and efficiently co-stimulate T cells.
- immunomodulatory compounds of the invention include, but are not limited to, cyano and carboxy derivatives of substituted styrenes such as those disclosed in U.S. Pat. No. 5,929,117; 1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl) isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines such as those described in U.S. Pat. No. 5,874,448; the tetra substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines described in U.S. Pat. No.
- aminothalidomide as well as analogs, hydrolysis products, metabolites, derivatives and precursors of aminothalidomide, and substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles such as those described in U.S. Pat. Nos. 6,281,230 and 6,316,471; isoindole-imide compounds such as those described in U.S. patent application Ser. No. 09/972,487 filed on Oct. 5, 2001, U.S. patent application Ser. No.
- Immunomodulatory compounds of the invention do not include thalidomide.
- immunomodulatory compounds of the invention include, but are not limited to, 1-oxo- and 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring as described in U.S. Pat. No. 5,635,517 which is incorporated herein by reference. These compounds have the structure I:
- immunomodulatory compounds include, but are not limited to:
- R 1 is hydrogen or methyl.
- the invention encompasses the use of enantiomerically pure forms (e.g. optically pure (R) or (S) enantiomers) of these compounds.
- one of X and Y is C ⁇ O and the other is CH 2 or C ⁇ O;
- R 1 is H, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3 , C(S)R 3 , C(O)OR 4 , (C 1 -C 8 )alkyl-N(R 6 ) 2 , (C 1 -C 8 )alkyl-OR 5 , (C 1 -C 8 )alkyl-C(O)OR 5 , C(O)NHR 3 , C(S)NHR 3 , C(O)NR 3 R 3′ , C(S)NR 3 R 3′
- R 2 is H, F, benzyl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl;
- R 3 and R 3′ are independently (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6 ) 2 , (C 1 -C 8 )alkyl-OR 5 , (C 1 -C 8 )alkyl-C(O)OR 5 , (C 1 -C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ;
- R 4 is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkyl-OR 5 , benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, or (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl;
- R 5 is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, or (C 2 -C 5 )heteroaryl;
- each occurrence of R 6 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 2 -C 5 )heteroaryl, or (C 0 -C 8 )alkyl-C(O)O—R 5 or the R 6 groups can join to form a heterocycloalkyl group;
- n 0 or 1
- R 1 is (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3 , C(O)OR 4 , (C 1 -C 8 )alkyl-N(R 6 ) 2 , (C 1 -C 8 )alkyl-OR 5 , (C 1 -C 8 )alkyl-C(O)OR S , C(S)NHR 3 , or (C 1 -C 8 )alkyl-O(CO)R 5 ;
- R 2 is H or (C 1 -C 8 )alkyl
- R 3 is (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 5 -C 8 )alkyl-N(R 6 ) 2 ; (C 0 -C 8 )alkyl-NH—C(O)O—R 5 ; (C 1 -C 8 )alkyl-OR 5 , (C 1 -C 8 )alkyl-C(O)OR 5 , (C 1 -C 8 )alkyl-O(CO)R 5 , or C(O)OR 5 ; and the other variables have the same definition
- R 2 is H or (C 1 -C 4 )alkyl.
- R 1 is (C 1 -C 8 )alkyl or benzyl.
- R 1 is H, (C 1 -C 8 )alkyl, benzyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , or
- R 1 is
- R 7 is independently H, (C 1 -C 8 )alkyl, benzyl, CH 2 OCH 3 , or CH 2 CH 2 OCH 3 .
- R 1 is C(O)R 3 .
- R 3 is (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 1 -C 8 )alkyl, aryl, or (C 0 -C 4 )alkyl-OR 5 .
- heteroaryl is pyridyl, furyl, or thienyl.
- R 1 is C(O)OR 4 .
- the H of C(O)NHC(O) can be replaced with (C 1 -C 4 )alkyl, aryl, or benzyl.
- one of X and Y is C ⁇ O and the other is CH 2 or C ⁇ O;
- R is H or CH 2 OCOR′
- each of R 1 , R 2 , R 3 , or R 4 independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R 1 , R 2 , R 3 , or R 4 is nitro or —NHR 5 and the remaining of R 1 , R 2 , R 3 , or R 4 are hydrogen;
- R 5 is hydrogen or alkyl of 1 to 8 carbons
- R 6 hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro;
- R′ is R 7 —CHR 10 —N(R 8 R 9 );
- R 7 is m-phenylene or p-phenylene or —(C n H 2n )— in which n has a value of 0 to 4;
- each of R 8 and R 9 taken independently of the other is hydrogen or alkyl of 1 to 8 carbon atoms, or R 8 and R 9 taken together are tetramethylene, pentamethylene, hexamethylene, or —CH 2 CH 2 [X]X 1 CH 2 CH 2 — in which [X]X 1 is —O—, —S—, or —NH—;
- R 10 is hydrogen, alkyl of to 8 carbon atoms, or phenyl
- the most preferred immunomodulatory compounds of the invention are 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione and 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione.
- the compounds can be obtained via standard, synthetic methods (see e.g., U.S. Pat. No. 5,635,517, incorporated herein by reference).
- the compounds are available from Celgene Corporation, Warren, N.J.
- 4-(Amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (ACTIMIDTM) has the following chemical structure:
- the compound 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (REVIMIDTM) has the following chemical structure:
- the term “pharmaceutically acceptable salt” encompasses non-toxic acid and base addition salts of the compound to which the term refers.
- Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases know in the art, which include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid, and the like.
- bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds are those that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations such as, but not limited to, alkali metal or alkaline earth metal salts and the calcium, magnesium, sodium or potassium salts in particular.
- Suitable organic bases include, but are not limited to, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine, and procaine.
- prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound.
- prodrugs include, but are not limited to, derivatives of immunomodulatory compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
- prodrugs include derivatives of immunomodulatory compounds of the invention that comprise —NO, —NO 2 , —ONO, or —ONO 2 moieties.
- Prodrugs can typically be prepared using well-known methods, such as those described in 1 Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York 1985).
- biohydrolyzable amide means an amide, ester, carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound.
- biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (such as acetoxylmethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyl-oxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylamino alkyl esters (such as acetamidomethyl esters).
- lower alkyl esters such as acetoxylmethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl est
- biohydrolyzable amides include, but are not limited to, lower alkyl amides, ⁇ -amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
- biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
- immunomodulatory compounds of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers or mixtures of diastereomers.
- This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms.
- mixtures comprising equal or unequal amounts of the enantiomers of a particular immunomodulatory compounds of the invention may be used in methods and compositions of the invention.
- These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents.
- stereomerically pure means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
- a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
- a stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
- a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
- stereomerically enriched means a composition that comprises greater than about 60% by weight of one stereoisomer of a compound, preferably greater than about 70% by weight, more preferably greater than about 80% by weight of one stereoisomer of a compound.
- enantiomerically pure means a stereomerically pure composition of a compound having one chiral center.
- stereomerically enriched means a stereomerically enriched composition of a compound having one chiral center.
- Immunomodulatory compounds can be combined with other pharmacologically active compounds (“second active agents”) in methods and compositions of the invention. It is believed that certain combinations work synergistically in the treatment of particular types of cancer and certain diseases and conditions associated with, or characterized by, undesired angiogenesis. Immunomodulatory compounds can also work to alleviate adverse effects associated with certain second active agents, and some second active agents can be used to alleviate adverse effects associated with immunomodulatory compounds.
- second active agents pharmacologically active compounds
- Second active ingredients or agents can be used in the methods and compositions of the invention together with an immunomodulatory compound.
- Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).
- large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies.
- Typical large molecule active agents are biological molecules, such as naturally occurring or artificially made proteins. Proteins that are particularly useful in this invention include proteins that stimulate the survival and/or proliferation of hematopoietic precursor cells and immunologically active poietic cells in vitro or in vivo. Others stimulate the division and differentiation of committed erythroid progenitors in cells in vitro or in vivo.
- interleukins such as IL-2 (including recombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18
- interferons such as interferon alfa-2a, interferon alfa-2b, interferon alfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-I b
- GM-CF and GM-CSF GM-CF and GM-CSF
- EPO EPO
- Recombinant and mutated forms of GM-CSF can be prepared as described in U.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; all of which are incorporated herein by reference.
- Recombinant and mutated forms of G-CSF can be prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755; all of which are incorporated herein by reference.
- This invention encompasses the use of native, naturally occurring, and recombinant proteins.
- the invention further encompasses mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit, in vivo, at least some of the pharmacological activity of the proteins upon which they are based.
- mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the proteins.
- mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the proteins.
- mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the proteins.
- mutants include carbohydrate moieties normally present in their naturally occurring forms (e.g., nonglycosylated forms).
- derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to the protein or active portion of the protein of interest. See, e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. Methods 248:91-101 (2001).
- Antibodies that can be used in combination with compounds of the invention include monoclonal and polyclonal antibodies.
- antibodies include, but are not limited to, trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (AvastinTM), pertuzumab (OmnitargTM), tositumomab (Bexxar®), edrecolomab (Panorex®), and G250.
- Compounds of the invention can also be combined with, or used in combination with, anti-TNF- ⁇ antibodies.
- cytokines such as IL-2, G-CSF, and GM-CSF
- cytokines such as IL-2, G-CSF, and GM-CSF
- IL-2, G-CSF, and GM-CSF can be used in the methods, pharmaceutical compositions, and kits of the invention. See, e.g., Emens, L. A., et al., Curr. Opinion Mol. Ther. 3(1):77-84 (2001).
- the large molecule active agent reduces, eliminates, or prevents an adverse effect associated with the administration of an immunomodulatory compound.
- adverse effects can include, but are not limited to, drowsiness and somnolence, dizziness and orthostatic hypotension, neutropenia, infections that result from neutropenia, increased HIV-viral load, bradycardia, Stevens-Johnson Syndrome and toxic epidermal necrolysis, and seizures (e.g., grand mal convulsions).
- a specific adverse effect is neutropenia.
- Second active agents that are small molecules can also be used to alleviate adverse effects associated with the administration of an immunomodulatory compound. However, like some large molecules, many are believed to be capable of providing a synergistic effect when administered with (e.g., before, after or simultaneously) an immunomodulatory compound.
- small molecule second active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids.
- anti-cancer agents include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chloramb
- anti-cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
- Specific second active agents include, but are not limited to, oblimersen (Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxe
- Methods of this invention encompass methods of treating, preventing and/or managing various types of cancer and diseases and disorders associated with, or characterized by, undesired angiogenesis.
- treating refers to the administration of a compound of the invention or other additional active agent after the onset of symptoms of the particular disease or disorder.
- preventing refers to the administration prior to the onset of symptoms, particularly to patients at risk of cancer, and other diseases and disorders associated with, or characterized by, undesired angiogenesis.
- prevention includes the inhibition of a symptom of the particular disease or disorder.
- patients with familial history of cancer and diseases and disorders associated with, or characterized by, undesired angiogenesis are preferred candidates for preventive regimens.
- the term “managing” encompasses preventing the recurrence of the particular disease or disorder in a patient who had suffered from it, and/or lengthening the time a patient who had suffered from the disease or disorder remains in remission.
- cancer includes, but is not limited to, solid tumors and blood born tumors.
- cancer refers to disease of skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone or blood, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus.
- Specific cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant giolma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-C
- the terms “diseases or disorders associated with, or characterized by, undesired angiogenesis”, “diseases or disorders associated with undesired angiogenesis”, and “diseases or disorders characterized by undesired angiogenesis” refer to diseases, disorders and conditions that are caused, mediated or attended by undesired, unwanted or uncontrolled angiogenesis, including, but not limited to, inflammatory diseases, autoimmune diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, and retina neovascular diseases.
- diseases or disorders associated with undesired angiogenesis include, but are not limited to, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, proliferative vitreoretinopathy, trachoma, myopia, optic pits, epidemnic keratoconjunctivitis, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis, syphilis, lipid degeneration, bacterial ulcer, fungal ulcer, Herpes simplex infection, Herpes zoster infection, protozoan infection, Kaposi sarcoma, Mooren ulcer, Terrien's marginal degeneration, mariginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, Wegeners
- diseases or disorders associated with undesired angiogenesis do not include congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, myocardial infarction, HIV, hepatitis, adult respiratory distress syndrome, bone-resorption disease, chronic obstructive pulmonary diseases, chronic pulmonary inflammatory disease, dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, meningitis, psoriasis, fibrotic disease, cachexia, graft rejection, rheumatoid spondylitis, osteoporosis, Crohn's disease, ulcerative colitis, inflammatory-bowel disease, multiple sclerosis, systemic lupus erythrematosus, erythema nodosum leprosum in lepro
- This invention encompasses methods of treating patients who have been previously treated for cancer or diseases or disorders associated with, or characterized by, undesired angiogenesis, but are non-responsive to standard therapies, as well as those who have not previously been treated.
- the invention also encompasses methods of treating patients regardless of patient's age, although some diseases or disorders are more common in certain age groups.
- the invention further encompasses methods of treating patients who have undergone surgery in an attempt to treat the disease or condition at issue, as well as those who have not. Because patients with cancer and diseases and disorders characterized by undesired angiogenesis have heterogenous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his/her prognosis.
- the skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual patient with cancer and other diseases or disorders.
- Methods encompassed by this invention comprise administering one or more immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, to a patient (e.g., a human) suffering, or likely to suffer, from cancer or a disease or disorder mediated by undesired angiogenesis.
- an immunomodulatory compound of the invention can be administered orally and in single or divided daily doses in an amount of from about 0.10 to about 150 mg/day.
- 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (ActimidTM) may be administered in an amount of from about 0.1 to about 1 mg per day, or alternatively from about 0.1 to about 5 mg every other day.
- 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl-piperidine-2,6-dione may be administered in an amount of from about 5 to 25 mg per day, or alternatively from about 10 to about 50 mg every other day.
- ActimidTM 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
- ActimidTM 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
- ActimidTM 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
- ActimidTM 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
- ActimidTM 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
- ActimidTM 4-(amino)-2-(2,6-dioxo(3-
- Specific methods of the invention comprise administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in combination with one or more second active agents, and/or in combination with radiation therapy, blood transfusions, or surgery.
- immunomodulatory compounds of the invention are disclosed herein (see, e.g., section 5.1).
- second active agents are also disclosed herein (see, e.g., section 5.2).
- Administration of the immunomodulatory compounds and the second active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration.
- the suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated.
- a preferred route of administration for an immunomodulatory compound of the invention is orally.
- Preferred routes of administration for the second active agents or ingredients of the invention are known to those of ordinary skill in the art. See, e.g., Physicians' Desk Reference, 1755-1760 (56 th ed., 2002).
- the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg.
- the specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount(s) of immunomodulatory compounds of the invention and any optional additional active agents concurrently administered to the patient.
- the second active agent is oblimersen (Genasense®), GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitor, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or a combination thereof.
- GM-CSF, G-CSF or EPO is administered subcutaneously during about five days in a four or six week cycle in an amount of from about 1 to about 750 mg/m 2 /day, preferably in an amount of from about 25 to about 500 mg/m 2 /day, more preferably in an amount of from about 50 to about 250 mg/m 2 /day, and most preferably in an amount of from about 50 to about 200 mg/m 2 /day.
- GM-C SF may be administered in an amount of from about 60 to about 500 mcg/m 2 intravenously over 2 hours, or from about 5 to about 12 mcg/m 2 /day subcutaneously.
- G-CSF may be administered subcutaneously in an amount of about 1 mcg/kg/day initially and can be adjusted depending on rise of total granulocyte counts.
- the maintenance dose of G-CSF may be administered in an amount of about 300 (in smaller patients) or 480 mcg subcutaneously.
- EPO may be administered subcutaneously in an amount of 10,000 Unit 3 times per week.
- RevimidTM in an amount of about 25 mg/d and dacarbazine in an amount of about from 200 to 1,000 mg/m 2 /d are administered to patients with metastatic malignant melanoma.
- RevimidTM is administered in an amount of from about 5 to about 25 mg/d to patients with metastatic malignant melanoma whose disease has progressed on treatment with dacarbazine, IL-2 or IFN.
- RevimidTM is administered to patients with relapsed or refractory multiple myeloma in an amount of about 15 mg/d twice a day or about 30 mg/d four times a day in a combination with dexamethasone.
- an immunomodulatory compound is administered with melphalan and dexamethasone to patients with amyloidosis.
- an immunomodulatory compound of the invention and steroids can be administered to patients with amyloidosis.
- an immunomodulatory compound is administered with gemcitabine and cisplatinum to patients with locally advanced or metastatic transitional cell bladder cancer.
- an immunomodulatory compound is administered in combination with a second active ingredient as follows: temozolomide to pediatric patients with relapsed or progressive brain tumors or recurrent neuroblastoma; celecoxib, etoposide and cyclophosphamide for relapsed or progressive CNS cancer; temodar to patients with recurrent or progressive meningioma, malignant meningioma, hemangiopericytoma, multiple brain metastases, relapased brain tumors, or newly diagnosed glioblastoma multiforms; irinotecan to patients with recurrent glioblastoma; carboplatin to pediatric patients with brain stem glioma; procarbazine to pediatric patients with progressive malignant gliomas; cyclophosphamide to patients with poor prognosis malignant brain tumors, newly diagnosed or recurrent glioblastoma multiforms; Gliadel® for high grade recurrent malignant gliomas;
- an immunomodulatory compound is administered with methotrexate and cyclophosphamide to patients with metastatic breast cancer.
- an immunomodulatory compound is administered with temozolomide to patients with neuroendocrine tumors.
- an immunomodulatory compound is administered with gemcitabine to patients with recurrent or metastatic head or neck cancer. In another embodiment, an immunomodulatory compound is administered with gemcitabine to patients with pancreatic cancer.
- an immunomodulatory compound is administered to patients with colon cancer in combination with Arisa®, taxol and/or taxotere.
- an immunomodulatory compound is administered with capecitabine to patients with refractory colorectal cancer or patients who fail first line therapy or have poor performance in colon or rectal adenocarcinoma.
- an immunomodulatory compound is administered in combination with fluorouracil, leucovorin, and irinotecan to patients with Dukes C & D colorectal cancer or to patients who have been previously treated for metastatic colorectal cancer.
- an immunomodulatory compound is administered to patients with refractory colorectal cancer in combination with capecitabine, xeloda, and/or CPT-11.
- an immunomodulatory compound of the invention is administered with capecitabine and irinotecan to patients with refractory colorectal cancer or to patients with unresectable or metastatic colorectal carcinoma.
- an immunomodulatory compound is administered alone or in combination with interferon alpha or capecitabine to patients with unresectable or metastatic hepatocellular carcinoma; or with cisplatin and thiotepa to patients with primary or metastatic liver cancer.
- an immunomodulatory compound is administered in combination with pegylated interferon alpha to patients with Kaposi's sarcoma.
- an immunomodulatory compound is administered in combination with fludarabine, carboplatin, and/or topotecan to patients with refractory or relapsed or high-risk acuted myelogenous leukemia.
- an immunomodulatory compound is administered in combination with liposomal daunorubicin, topotecan and/or cytarabine to patients with unfavorable karotype acute myeloblastic leukemia.
- an immunomodulatory compound is administered in combination with gemcitabine and irinotecan to patients with non-small cell lung cancer.
- an immunomodulatory compound is administered in combination with carboplatin and irinotecan to patients with non-small cell lung cancer.
- an immunomodulatory compound is administered with doxetaxol to patients with non-small cell lung cancer who have been previously treated with carbo/VP 16 and radiotherapy.
- an immunomodulatory compound is administered in combination with carboplatin and/or taxotere, or in combination with carboplatin, pacilitaxel and/or thoracic radiotherapy to patients with non-small cell lung cancer.
- an immunomodulatory compound is administered in combination with taxotere to patients with stage IIIB or IV non-small cell lung cancer.
- an immunomodulatory compound of the invention is administered in combination with oblimersen (Genasense®) to patients with small cell lung cancer.
- an immunomodulatory compound is administered alone or in combination with a second active ingredient such as vinblastine or fludarabine to patients with various types of lymphoma, including, but not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low grade follicular lymphoma.
- a second active ingredient such as vinblastine or fludarabine
- an immunomodulatory compound is administered in combination with taxotere, IL-2, IFN, GM-CSF, and/or dacarbazine to patients with various types or stages of melanoma.
- an immunomodulatory compound is administered alone or in combination with vinorelbine to patients with malignant mesothelioma, or stage IIIB non-small cell lung cancer with pleural implants or malignant pleural effusion mesothelioma syndrome.
- an immunomodulatory compound is administered to patients with various types or stages of multiple myeloma in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan, cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, or a combination thereof.
- an immunomodulatory compound is administered to patients with relapsed or refractory multiple myeloma in combination with doxorubicin (Doxil®), vincristine and/or dexamethasone (Decadron®).
- an immunomodulatory compound is administered to patients with various types or stages of ovarian cancer such as peritoneal carcinoma, papillary serous carcinoma, refractory ovarian cancer or recurrent ovarian cancer, in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or a combination thereof.
- an immunomodulatory compound is administered to patients with various types or stages of prostate cancer, in combination with xeloda, 5 FU/LV, gemcitabine, irinotecan plus gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, or a combination thereof.
- an immunomodulatory compound is administered to patients with various types or stages of renal cell cancer, in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination thereof.
- an immunomodulatory compound is administered to patients with various types or stages of gynecologic, uterus or soft tissue sarcoma cancer in combination with IFN, a COX-2 inhibitor such as Celebrex®, and/or sulindac.
- an immunomodulatory compound is administered to patients with various types or stages of solid tumors in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
- an immunomodulatory compound is administered to patients with scleroderma or cutaneous vasculitis in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
- This invention also encompasses a method of increasing the dosage of an anti-cancer drug or agent that can be safely and effectively administered to a patient, which comprises administering to a patient (e.g., a human) an immunomodulatory compound of the invention, or a pharmaceutically acceptable derivative, salt, solvate, clathrate, hydrate, or prodrug thereof.
- a patient e.g., a human
- an immunomodulatory compound of the invention or a pharmaceutically acceptable derivative, salt, solvate, clathrate, hydrate, or prodrug thereof.
- Patients that can benefit by this method are those likely to suffer from an adverse effect associated with anti-cancer drugs for treating a specific cancer of the skin, subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas, adrenal, kidney, prostate, breast, colorectal, or combinations thereof.
- the administration of an immunomodulatory compound of the invention alleviates or reduces adverse effects which are of such severity that it would otherwise limit the
- an immunomodulatory compound of the invention can be administered orally and daily in an amount of from about 0.1 to about 150 mg, and preferably from about 1 to about 50 mg, more preferably from about 2 to about 25 mg prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient.
- an immunomodulatory compound of the invention is administered in combination with specific agents such as heparin, aspirin, coumadin, or G-CSF to avoid adverse effects that are associated with anti-cancer drugs such as but not limited to neutropenia or thrombocytopenia.
- an immunomodulatory compound of the invention can be administered to patients with diseases and disorders associated with, or characterized by, undesired angiogenesis in combination with additional active ingredients including but not limited to anti-cancer drugs, anti-inflammatories, antihistamines, antibiotics, and steroids.
- this invention encompasses a method of treating, preventing and/or managing cancer, which comprises administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in conjunction with (e.g. before, during, or after) conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug based therapy presently used to treat, prevent or manage cancer.
- conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug based therapy presently used to treat, prevent or manage cancer.
- the invention encompasses a method of reducing, treating and/or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy.
- One or more immunomodulatory compounds of the invention and other active ingredient can be administered to a patient prior to, during, or after the occurrence of the adverse effect associated with conventional therapy.
- an immunomodulatory compound of the invention can be administered in an amount of from about 0.1 to about 150 mg, and preferably from about 1 to about 25 mg, more preferably from about 2 to about 10 mg orally and daily alone, or in combination with a second active agent disclosed herein (see, e.g., section 5.2), prior to, during, or after the use of conventional therapy.
- an immunomodulatory compound of the invention and doxetaxol are administered to patients with non-small cell lung cancer who were previously treated with carbo/VP 16 and radiotherapy.
- the invention encompasses a method of treating, preventing and/or managing cancer, which comprises administering the immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in conjunction with transplantation therapy.
- GVHD Graft Versus Host Disease
- an immunomodulatory compound of the invention exhibits immunomodulatory activity that may provide additive or synergistic effects when given concurrently with transplantation therapy in patients with cancer.
- An immunomodulatory compound of the invention can work in combination with transplantation therapy reducing complications associated with the invasive procedure of transplantation and risk of GVHD.
- This invention encompasses a method of treating, preventing and/or managing cancer which comprises administering to a patient (e.g., a human) an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, before, during, or after the transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow.
- stem cells suitable for use in the methods of the invention are disclosed in U.S. provisional patent application No. 60/372,348, filed Apr. 12, 2002 by R. Hariri et al., the entirety of which is incorporated herein by reference.
- an immunomodulatory compound of the invention is administered to patients with multiple myeloma before, during, or after the transplantation of autologous peripheral blood progenitor cell.
- an immunomodulatory compound is administered to patients with relapsing multiple myeloma after the stem cell transplantation.
- an immunomodulatory compound and prednisone are administered as maintenance therapy to patients with multiple myeloma following the transplantation of autologous stem cell.
- an immunomodulatory compound and dexamethasone are administered as salvage therapy for low risk post transplantation to patients with multiple myeloma.
- an immunomodulatory compound and dexamethasone are administered as maintenance therapy to patients with multiple myeloma following the transplantation of autologous bone marrow.
- an immunomodulatory compound is administered following the administration of high dose of melphalan and the transplantation of autologous stem cell to patients with chemotherapy responsive multiple myeloma.
- an immunomodulatory compound and PEG INTRO-A are administered as maintenance therapy to patients with multiple myeloma following the transplantation of autologous CD34-selected peripheral stem cell.
- an immunomodulatory compound is administered with post transplant consolidation chemotherapy to patients with newly diagnosed multiple myeloma to evaluate anti-angiogenesis.
- an immunomodulatory compound and dexamethasone are administered as maintenance therapy after DCEP consolidation, following the treatment with high dose of melphalan and the transplantation of peripheral blood stem cell to 65 years of age or older patients with multiple myeloma.
- the prophylactic or therapeutic agents of the invention are cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
- an immunomodulatory compound of the invention is administered daily in a single or divided doses in a four to six week cycle with a rest period of about a week or two weeks.
- the invention further allows the frequency, number, and length of dosing cycles to be increased.
- another specific embodiment of the invention encompasses the administration of an immunomodulatory compound of the invention for more cycles than are typical when it is administered alone.
- an immunomodulatory compound of the invention is administered for a greater number of cycles that would typically cause dose-limiting toxicity in a patient to whom a second active ingredient is not also being administered.
- an immunomodulatory compound of the invention is administered daily and continuously for three or four weeks at a dose of from about 0.1 to about 150 mg/d followed by a break of one or two weeks.
- ActimidTM is preferably administered daily and continuously at an initial dose of 0.1 to 5 mg/d with dose escalation (every week) by 1 to 10 mg/d to a maximum dose of 50 mg/d for as long as therapy is tolerated.
- RevimidTM is administered in an amount of about 5, 10, or 25 mg/day, preferably in an amount of about 10 mg/day for three to four weeks, followed by one week or two weeks of rest in a four or six week cycle.
- an immunomodulatory compound of the invention and a second active ingredient are administered orally, with administration of an immunomodulatory compound of the invention occurring 30 to 60 minutes prior to a second active ingredient, during a cycle of four to six weeks.
- the combination of an immunomodulatory compound of the invention and a second active ingredient is administered by intravenous infusion over about 90 minutes every cycle.
- one cycle comprises the administration of from about 10 to about 25 mg/day of RevimidTM and from about 50 to about 200 mg/m 2 /day of a second active ingredient daily for three to four weeks and then one or two weeks of rest.
- each cycle comprises the administration of from about 5 to about 10 mg/day of ActimidTM and from about 50 to about 200 mg/m 2 /day of a second active ingredient for 3 to 4 weeks followed by one or two weeks of rest.
- the number of cycles during which the combinatorial treatment is administered to a patient will be from about one to about 24 cycles, more typically from about two to about 16 cycles, and even more typically from about four to about three cycles.
- compositions can be used in the preparation of individual, single unit dosage forms.
- Pharmaceutical compositions and dosage forms of the invention comprise an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
- Pharmaceutical compositions and dosage forms of the invention can further comprise one or more excipients.
- compositions and dosage forms of the invention can also comprise one or more additional active ingredients. Consequently, pharmaceutical compositions and dosage forms of the invention comprise the active ingredients disclosed herein (e.g., an immunomodulatory compound and a second active agent). Examples of optional second, or additional, active ingredients are disclosed herein (see, e.g., section 5.2).
- Single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal or transcutaneous administration to a patient.
- mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
- parenteral e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial
- topical e.g., eye drops or other ophthalmic preparations
- transdermal or transcutaneous administration e.g., transcutaneous administration to a patient.
- dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
- suspensions e.g., aqueous or non-aqueous liquid suspensions, oil-in-water e
- composition, shape, and type of dosage forms of the invention will typically vary depending on their use.
- a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease.
- a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease.
- Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
- Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient.
- oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms.
- the suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water.
- lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
- Lactose-free compositions of the invention can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002).
- lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
- Preferred lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
- This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
- water e.g., 5%
- water is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80.
- water and heat accelerate the decomposition of some compounds.
- the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
- Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
- Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
- anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
- compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
- compounds which are referred to herein as “stabilizers”, include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
- the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients.
- typical dosage forms of the invention comprise an immunomodulatory compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in an amount of from about 0.10 to about 150 mg.
- Typical dosage forms comprise an immunomodulatory compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150 or 200 mg.
- a preferred dosage form comprises 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (ActimidTM) in an amount of about 1, 2, 5, 10, 25 or 50 mg.
- ActimidTM 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
- ActimidTM is 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
- ActimidTM isoindoline-1,3-dione
- a preferred dosage form comprises 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (RevimidTM) in an amount of about 5, 10, 25 or 50 mg.
- Typical dosage forms comprise
- compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
- dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).
- Typical oral dosage forms of the invention are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
- Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
- excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
- excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
- tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
- a tablet can be prepared by compression or molding.
- Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.
- Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants.
- Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
- Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof.
- An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581.
- Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
- fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
- the binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
- Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention.
- the amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
- Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.
- Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
- Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
- calcium stearate e.g., magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc
- hydrogenated vegetable oil e.g., peanut oil, cottonseed oil
- Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
- AEROSIL200 a syloid silica gel
- a coagulated aerosol of synthetic silica marketed by Degussa Co. of Plano, Tex.
- CAB-O-SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.
- a preferred solid oral dosage form of the invention comprises an immunomodulatory compound of the invention, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
- Active ingredients of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference.
- Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
- Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
- the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
- controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
- the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
- Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
- controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
- Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
- the drug In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
- Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
- Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
- Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
- water for Injection USP Water for Injection USP
- aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride
- cyclodextrin and its derivatives can be used to increase the solubility of an immunomodulatory compound of the invention and its derivatives. See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein by reference.
- Topical and mucosal dosage forms of the invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th and 18 th eds., Mack Publishing, Easton Pa. (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
- Suitable excipients e.g., carriers and diluents
- other materials that can be used to provide topical and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
- typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable.
- Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16 th and 18 th eds., Mack Publishing, Easton Pa. (1980 & 1990).
- the pH of a pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients.
- the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
- Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
- stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent.
- Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
- active ingredients of the invention are preferably not administered to a patient at the same time or by the same route of administration.
- This invention therefore encompasses kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.
- kits encompassed by this invention can further comprise additional active ingredients such as oblimersen (Genasense®), melphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitor, pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13 cis-retinoic acid, or a pharmacologically active mutant or derivative thereof, or a combination thereof.
- additional active ingredients include, but are not limited to, those disclosed herein (see, e.g., section 5.2).
- Kits of the invention can further comprise devices that are used to administer the active ingredients.
- devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
- Kits of the invention can further comprise cells or blood for transplantation as well as pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
- the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
- Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
- aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
- water-miscible vehicles such as, but not limited to, ethyl alcohol
- the IC 50 's of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione for inhibiting production of TNF- ⁇ following LPS-stimulation of PBMC and human whole blood were ⁇ 24 nM (6.55 ng/mL) and ⁇ 25 nM (6.83 ng/mL), respectively.
- In vitro studies suggest a pharmacological activity profile for 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that is similar to, but at least 200 times more potent than, thalidomide.
- the IC 50 's of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for inhibiting production of TNF- ⁇ following LPS-stimulation of PBMC and human whole blood were ⁇ 100 nM (25.9 ng/mL) and ⁇ 480 nM (103.6 ng/mL), respectively.
- Thalidomide in contrast, had an IC 50 of ⁇ 194 ⁇ M (50.2 ⁇ g/mL) for inhibiting production of TNF- ⁇ following LPS-stimulation of PBMC.
- 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is also approximately 50 to 100 times more potent than thalidomide in augmenting the production of IL-2 and IFN- ⁇ following TCR activation of PBMC (IL-2) or T-cells (IFN- ⁇ ).
- 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione exhibited dose-dependent inhibition of LPS-stimulated production of the pro-inflammatory cytokines TNF- ⁇ , IL-1 ⁇ , and IL-6 by PBMC while it increased production of the anti-inflammatory cytokine IL-10.
- doses of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione or vehicle are successively administered via infusion through the jugular vein separated by intervals of at least 30 minutes.
- an immunomodulatory compound of the invention are cyclically administered to patients with cancer. Cycling therapy involves the administration of a first agent for a period of time, followed by a rest for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
- prophylactic or therapeutic agents are administered in a cycle of about 4 to 6 weeks, about once or twice every day.
- One cycle can comprise the administration of a therapeutic on prophylactic agent for three to four weeks and at least a week or two weeks of rest.
- the number of cycles administered is from about one to about 24 cycles, more typically from about two to about 16 cycles, and more typically from about four to about eight cycles.
- SWOG Southwest Oncology Group
- Relapse following remission is defined as >25% increase in M component from baseline levels; reappearance of the M paraprotein that had previously disappeared; or a definite increase in the size and number of lytic bone lesions recognized on radiographs.
- Patients may have had prior therapy with thalidomide, provided they were able to tolerate the treatment.
- a Zubrod performance status of 0 to 2 is required for all patients.
- 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione is administered to patients at doses of 1, 2, 5, or 10 mg/day for up to four weeks; at each dose level, three patients are initially enrolled. Dosing occurs at approximately the same time each morning; all doses are administered in the fasted state (no eating for at least two hours prior to dosing and two hours after dosing).
- 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione doses are administered in an ascending fashion such that patients in the first cohort receive the lowest dose of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (1 mg/day) and escalation to the next higher dose level occurs only following the establishment of safety and tolerability at the current dose. If one out of three patients at any dose level experience dose limiting toxicity (DLT), three additional patients are enrolled at that dose.
- DLT dose limiting toxicity
- Blood sampling for analysis of pharmacokinetic parameters is performed on Days 1 and 28 according to the following sampling schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose.
- An additional blood sample is collected at each weekly visit for the determination of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione levels.
- Total urine collections are also made with urine pooled according to the following time intervals post-dose: 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours.
- Safety assessments are made by monitoring adverse events, vital signs, ECGs, clinical laboratory evaluations (blood chemistry, hematology, lymphocyte phenotyping, and urinalysis), and physical examination at specific times during the study.
- DLT dose limiting toxicity
- Blood and urine samples were collected for analysis of pharmacokinetic parameters on Days 1 and 28. Blood samples were collected according to the following sampling schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose. In addition, a blood sample was collected at each weekly clinic visit for 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione determination. Total urine was collected and pooled according to the following time intervals post-dose: 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours.
- the first cohort of 3 patients was treated for 28 days at 5 mg/day without any dose limiting toxicity (DLT).
- the second cohort of 3 patients subsequently commenced therapy at 10 mg/day.
- Patients in the second 10 mg/day of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione cohort tolerated treatment well.
- the study of Phase 1 study was designed to determine a maximum tolerated dose (MTD) of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in patients with refractory solid tumors and/or lymphoma, as well as to characterize the pharmacokinetic and side effect profiles of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in this patient population.
- the study design dictates that at least 3 patients must be enrolled at a dose level and have completed 28 days of treatment prior to enrollment of patients at the next higher dose level.
- Patients in the first cohort began dosing at 5 mg/day of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. Patients will be escalated to 10, 20, 25, and 30 mg/day provided there is no toxicity.
- the MTD is defined as the highest dose level in which fewer than two of six patients treated did not experience Grade 3 or greater non-hematological toxicity or Grade 4 or greater hematological toxicity. If, at any given dose level in either study, one out of three patients experiences toxicity, three additional patients must be treated at that particular dose. If, however, two out of six patients experience DLT, the MTD is judged to have been exceeded. No further dose escalations are to occur and additional patients are to be enrolled at the previous dose level.
- the dose of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione administered is escalated until the MTD is achieved or the maximum daily dose of is reached.
- This study was performed to find toxicity in patients with recurrent, high-grade gliomas.
- the study is designed such that patients are given increasingly higher doses of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione until a maximum tolerated dose (MTD) is established.
- MTD maximum tolerated dose
- the study also seeks to obtain preliminary toxicity information and pharmacokinetic data on 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, as well as to develop exploratory data concerning surrogate end points of angiogenic activity in vivo using functional neuro-imaging studies, and in vitro assays of serum angiogenic peptides.
- Patients enrolled in the first cohort receive 2.5 mg/m 2 /day for a 4-week cycle.
- 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione administered once daily for 3 weeks followed by a week of rest.
- Patients who complete a treatment cycle may receive another cycle of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione treatment if two criteria are met.
- the patient must have stable disease or have experienced a partial response or complete response, or the patient is benefiting from the therapy with 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as evidenced by a decrease in tumor-related symptoms such as neurological deficits.
- the patient must have recovered from toxicity related to 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione which occurred in the prior cycle by Day 42 or sooner (28-day cycle plus limit of 2 weeks to recover) as evidenced by a return to Grade ⁇ 1 toxicity level.
- DLT is defined as an non-hematological event Grade ⁇ 3 toxicity or hematological event of Grade 4 toxicity thought to be related to the study medication. Patients who experience DLT in the first cycle and have no response to therapy are removed from the study.
- 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione doses are subsequently escalated to 5, 8, 11, 15, and 20 mg/m 2 /day to a maximum total daily dose of 40 mg.
- Patients continue to receive 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione on a 4-week cycle per dose level until one of the off-study criteria are met.
- Three patients are enrolled in each cohort. If at least one DLT occurs, three additional patients are added to the cohort at that particular dose level. If two DLTs occur, the MTD, defined as the dose at which fewer than one-third of patients at each dose level experiences DLT has been exceeded and four more patients are treated at the previous dose.
- Pharmacokinetic sampling is performed prior the first dose of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Day 1) and 0.5, 1, 2, 4, 6, 8, 24, and 48 hours thereafter. Sampling is also conducted pre-dose on Days 7 and 21 and 0.5, 1, 2, 4, 6, 8, and 24 post-dose on Day 21 to evaluate steady-state 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione levels.
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Abstract
Methods of treating, preventing and/or managing cancer as well as and diseases and disorders associated with, or characterized by, undesired angiogenesis are disclosed. Specific methods encompass the administration of an immunomodulatory compound alone or in combination with a second active ingredient. The invention further relates to methods of reducing or avoiding adverse side effects associated with chemotherapy, radiation therapy, hormonal therapy, biological therapy or immunotherapy which comprise the administration of an immunomodulatory compound. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in methods of the invention are also disclosed.
Description
This application is a continuation application of U.S. patent application No. 10/438,213, filed May 15, 2003 now U.S. Pat. No. 7,968,569, presently pending, which claims the benefit of U.S. provisional application nos. 60/380,842, filed May 17, 2002, and 60/424,600, filed Nov. 6, 2002, the entireties of which are incorporated herein by reference.
This invention relates to methods of treating, preventing and/or managing specific cancers, and other diseases including, but not limited to, those associated with, or characterized by, undesired angiogenesis, by the administration of one or more immunomodulatory compounds alone or in combination with other therapeutics. In particular, the invention encompasses the use of specific combinations, or “cocktails”, of drugs and other therapy, e.g., radiation to treat these specific cancers, including those refractory to conventional therapy. The invention also relates to pharmaceutical compositions and dosing regimens.
Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia. The neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host's immune surveillance. Roitt, I., Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).
There is an enormous variety of cancers which are described in detail in the medical literature. Examples includes cancer of the lung, colon, rectum, prostate, breast, brain, and intestine. The incidence of cancer continues to climb as the general population ages, as new cancers develop, and as susceptible populations (e.g., people infected with AIDS or excessively exposed to sunlight) grow. A tremendous demand therefore exists for new methods and compositions that can be used to treat patients with cancer.
Many types of cancers are associated with new blood vessel formation, a process known as angiogenesis. Several of the mechanisms involved in tumor-induced angiogenesis have been elucidated. The most direct of these mechanisms is the secretion by the tumor cells of cytokines with angiogenic properties. Examples of these cytokines include acidic and basic fibroblastic growth factor (a,b-FGF), angiogenin, vascular endothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cells can release angiogenic peptides through the production of proteases and the subsequent breakdown of the extracellular matrix where some cytokines are stored (e.g., b-FGF). Angiogenesis can also be induced indirectly through the recruitment of inflammatory cells (particularly macrophages) and their subsequent release of angiogenic cytokines (e.g., TNF-α, bFGF).
A variety of other diseases and disorders are also associated with, or characterized by, undesired angiogenesis. For example, enhanced or unregulated angiogenesis has been implicated in a number of diseases and medical conditions including, but not limited to, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, rubeosis (neovascularization of the angle), viral diseases, genetic diseases, inflammatory diseases, allergic diseases, and autoimmune diseases. Examples of such diseases and conditions include, but are not limited to: diabetic retinopathy; retinopathy of prematurity; corneal graft rejection; neovascular glaucoma; retrolental fibroplasia; and proliferative vitreoretinopathy.
Accordingly, compounds that can control angiogenesis or inhibit the production of certain cytokines, including TNF-α, may be useful in the treatment and prevention of various diseases and conditions.
Current cancer therapy may involve surgery, chemotherapy, hormonal therapy and/or radiation treatment to eradicate neoplastic cells in a patient (see, for example, Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV). Recently, cancer therapy could also involve biological therapy or immunotherapy. All of these approaches pose significant drawbacks for the patient. Surgery, for example, may be contraindicated due to the health of a patient or may be unacceptable to the patient. Additionally, surgery may not completely remove neoplastic tissue. Radiation therapy is only effective when the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue. Radiation therapy can also often elicit serious side effects. Hormonal therapy is rarely given as a single agent. Although hormonal therapy can be effective, it is often used to prevent or delay recurrence of cancer after other treatments have removed the majority of cancer cells. Biological therapies and immunotherapies are limited in number and may produce side effects such as rashes or swellings, flu-like symptoms, including fever, chills and fatigue, digestive tract problems or allergic reactions.
With respect to chemotherapy, there are a variety of chemotherapeutic agents available for treatment of cancer. A majority of cancer chemotherapeutics act by inhibiting DNA synthesis, either directly, or indirectly by inhibiting the biosynthesis of deoxyribonucleotide triphosphate precursors, to prevent DNA replication and concomitant cell division. Gilman et al., Goodman and Gilman's: The Pharmacological Basis of Therapeutics, Tenth Ed. (McGraw Hill, New York).
Despite availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant, and often dangerous side effects including severe nausea, bone marrow depression, and immunosuppression. Additionally, even with administration of combinations of chemotherapeutic agents, many tumor cells are resistant or develop resistance to the chemotherapeutic agents. In fact, those cells resistant to the particular chemotherapeutic agents used in the treatment protocol often prove to be resistant to other drugs, even if those agents act by different mechanism from those of the drugs used in the specific treatment. This phenomenon is referred to as pleiotropic drug or multidrug resistance. Because of the drug resistance, many cancers prove refractory to standard chemotherapeutic treatment protocols.
Other diseases or conditions associated with, or characterized by, undesired angiogenesis are also difficult to treat. However, some compounds such as protamine, hepain and steroids have been proposed to be useful in the treatment of certain specific diseases. Taylor et al., Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and U.S. Pat. Nos. 5,001,116 and 4,994,443. Thalidomide and certain derivatives of it have also been proposed for the treatment of such diseases and conditions. U.S. Pat. Nos. 5,593,990, 5,629,327, 5,712,291, 6,071,948 and 6,114,355 to D′Amato.
Still, there is a significant need for safe and effective methods of treating, preventing and managing cancer and other diseases and conditions, particularly for diseases that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and hormonal therapy, while reducing or avoiding the toxicities and/or side effects associated with the conventional therapies.
A number of studies have been conducted with the aim of providing compounds that can safely and effectively be used to treat diseases associated with abnormal production of TNF-α. See, e.g., Marriott, J. B., et al., Expert Opin. Biol. Ther. 1(4):1-8 (2001); G. W. Muller, et al., Journal of Medicinal Chemistry 39(17): 3238-3240 (1996); and G. W. Muller, et al., Bioorganic & Medicinal Chemistry Letters 8: 2669-2674 (1998). Some studies have focused on a group of compounds selected for their capacity to potently inhibit TNF-α production by LPS stimulated PBMC. L. G. Corral, et al., Ann. Rheum. Dis. 58:(Suppl I) 1107-1113 (1999). These compounds, which are referred to as IMiDs™ (Celgene Corporation) or Immunomodulatory Drugs, show not only potent inhibition of TNF-α but also marked inhibition of LPS induced monocyte IL1β and IL12 production. LPS induced IL6 is also inhibited by immunomodulatory compounds, albeit partially. These compounds are potent stimulators of LPS induced IL10. Id. Particular examples of IMiD™s include, but are not limited to, the substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles described in U.S. Pat. Nos. 6,281,230 and 6,316,471, both to G. W. Muller, et al.
This invention encompasses methods of treating and preventing certain types of cancer, including primary and metastatic cancer, as well as cancers that are refractory or resistant to conventional chemotherapy. The methods comprise administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The invention also encompasses methods of managing certain cancers (e.g., preventing or prolonging their recurrence, or lengthening the time of remission) which comprise administering to a patient in need of such management a prophylactically effective amount of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
In particular methods of the invention, an immunomodulatory compound is administered in combination with a therapy conventionally used to treat, prevent or manage cancer. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy.
This invention also encompasses methods of treating, managing or preventing diseases and disorders other than cancer that are associated with, or characterized by, undesired angiogenesis, which comprise administering to a patient in need of such treatment, management or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
In other methods of the invention, an immunomodulatory compound is administered in combination with a therapy conventionally used to treat, prevent or manage diseases or disorders associated with, or characterized by, undesired angiogenesis. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy.
This invention encompasses pharmaceutical compositions, single unit dosage forms, dosing regimens and kits which comprise an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second, or additional, active agent. Second active agents include specific combinations, or “cocktails”, of drugs.
A first embodiment of the invention encompasses methods of treating, managing, or preventing cancer which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
In particular methods encompassed by this embodiment, the immunomodulatory compound is administered in combination with another drug (“second active agent”) or method of treating, managing, or preventing cancer. Second active agents include small molecules and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells. Methods, or therapies, that can be used in combination with the administration of the immunomodulatory compound include, but are not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy, and other non-drug based therapies presently used to treat, prevent or manage cancer.
Another embodiment of the invention encompasses methods of treating, managing or preventing diseases and disorders other than cancer that are characterized by undesired angiogenesis. These methods comprise the administration of a therapeutically or prophylactically effective amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
Examples of diseases and disorders associated with, or characterized by, undesired angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, and rubeosis (neovascularization of the angle).
In particular methods encompassed by this embodiment, the immunomodulatory compound is administer in combination with a second active agent or method of treating, managing, or preventing the disease or condition. Second active agents include small molecules and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells. Methods, or therapies, that can be used in combination with the administration of the immunomodulatory compound include, but are not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy, and other non-drug based therapies presently used to treat, prevent or manage disease and conditions associated with, or characterized by, undesired angiogenesis.
The invention also encompasses pharmaceutical compositions (e.g., single unit dosage forms) that can be used in methods disclosed herein. Particular pharmaceutical compositions comprise an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active agent.
Compounds used in the invention include immunomodulatory compounds that are racemic, stereomerically enriched or stereomerically pure, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof. Preferred compounds used in the invention are small organic molecules having a molecular weight less than about 1,000 g/mol, and are not proteins, peptides, oligonucleotides, oligosaccharides or other macromolecules.
As used herein and unless otherwise indicated, the terms “immunomodulatory compounds” and “IMiDs™” (Celgene Corporation) encompasses small organic molecules that markedly inhibit TNF-α, LPS induced monocyte IL1β and IL12, and partially inhibit IL6 production. Specific immunomodulatory compounds are discussed below.
TNF-α is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. TNF-α is responsible for a diverse range of signaling events within cells. TNF-α may play a pathological role in cancer. Without being limited by theory, one of the biological effects exerted by the immunomodulatory compounds of the invention is the reduction of synthesis of TNF-α. Immunomodulatory compounds of the invention enhance the degradation of TNF-α mRNA.
Further, without being limited by theory, immunomodulatory compounds used in the invention may also be potent co-stimulators of T cells and increase cell proliferation dramatically in a dose dependent manner. Immunomodulatory compounds of the invention may also have a greater co-stimulatory effect on the CD8+ T cell subset than on the CD4+ T cell subset. In addition, the compounds preferably have anti-inflammatory properties, and efficiently co-stimulate T cells.
Specific examples of immunomodulatory compounds of the invention, include, but are not limited to, cyano and carboxy derivatives of substituted styrenes such as those disclosed in U.S. Pat. No. 5,929,117; 1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl) isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines such as those described in U.S. Pat. No. 5,874,448; the tetra substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines described in U.S. Pat. No. 5,798,368; 1-oxo and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines (e.g., 4-methyl derivatives of thalidomide and EM-12), including, but not limited to, those disclosed in U.S. Pat. No. 5,635,517; and a class of non-polypeptide cyclic amides disclosed in U.S. Pat. Nos. 5,698,579 and 5,877,200; analogs and derivatives of thalidomide, including hydrolysis products, metabolites, derivatives and precursors of thalidomide, such as those described in U.S. Pat. Nos. 5,593,990, 5,629,327, and 6,071,948 to D'Amato; aminothalidomide, as well as analogs, hydrolysis products, metabolites, derivatives and precursors of aminothalidomide, and substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles such as those described in U.S. Pat. Nos. 6,281,230 and 6,316,471; isoindole-imide compounds such as those described in U.S. patent application Ser. No. 09/972,487 filed on Oct. 5, 2001, U.S. patent application Ser. No. 10/032,286 filed on Dec. 21, 2001, and International Application No. PCT/US01/50401 (International Publication No. WO 02/059106). The entireties of each of the patents and patent applications identified herein are incorporated herein by reference. Immunomodulatory compounds of the invention do not include thalidomide.
Other specific immunomodulatory compounds of the invention include, but are not limited to, 1-oxo- and 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring as described in U.S. Pat. No. 5,635,517 which is incorporated herein by reference. These compounds have the structure I:
in which one of X and Y is C═O, the other of X and Y is C═O or CH2, and R2 is hydrogen or lower alkyl, in particular methyl. Specific immunomodulatory compounds include, but are not limited to:
1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline;
1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline;
1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline;
1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline;
1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and
1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.
Other specific immunomodulatory compounds of the invention belong to a class of substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles, such as those described in U.S. Pat. Nos. 6,281,230; 6,316,471; 6,335,349; and 6,476,052, and International Patent Application No. PCT/US97/13375 (International Publication No. WO 98/03502), each of which is incorporated herein by reference. Compounds representative of this class are of the formulas:
wherein R1 is hydrogen or methyl. In a separate embodiment, the invention encompasses the use of enantiomerically pure forms (e.g. optically pure (R) or (S) enantiomers) of these compounds.
Still other specific immunomodulatory compounds of the invention belong to a class of isoindole-imides disclosed in U.S. patent application Ser. Nos. 10/032,286 and 09/972,487, and International Application No. PCT/US01/50401 (International Publication No. WO 02/059106), each of which are incorporated herein by reference. Representative compounds are of formula II:
and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:
one of X and Y is C═O and the other is CH2 or C═O;
R1 is H, (C1-C8)alkyl, (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C0-C4)alkyl-(C1-C6)heterocycloalkyl, (C0-C4)alkyl-(C2-C5)heteroaryl, C(O)R3, C(S)R3, C(O)OR4, (C1-C8)alkyl-N(R6)2, (C1-C8)alkyl-OR5, (C1-C8)alkyl-C(O)OR5, C(O)NHR3, C(S)NHR3, C(O)NR3R3′, C(S)NR3R3′ or (C1-C8)alkyl-O(CO)R5;
R2 is H, F, benzyl, (C1-C8)alkyl, (C2-C8)alkenyl, or (C2-C8)alkynyl;
R3 and R3′ are independently (C1-C8)alkyl, (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C0-C4)alkyl-(C1-C6)heterocycloalkyl, (C0-C4)alkyl-(C2-C5)heteroaryl, (C0-C8)alkyl-N(R6)2, (C1-C8)alkyl-OR5, (C1-C8)alkyl-C(O)OR5, (C1-C8)alkyl-O(CO)R5, or C(O)OR5;
R4 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkyl-OR5, benzyl, aryl, (C0-C4)alkyl-(C1-C6)heterocycloalkyl, or (C0-C4)alkyl-(C2-C5)heteroaryl;
R5 is (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, or (C2-C5)heteroaryl;
each occurrence of R6 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C2-C5)heteroaryl, or (C0-C8)alkyl-C(O)O—R5 or the R6 groups can join to form a heterocycloalkyl group;
n is 0 or 1; and
* represents a chiral-carbon center.
In specific compounds of formula II, when n is 0 then R1 is (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C0-C4)alkyl-(C1-C6)heterocycloalkyl, (C0-C4)alkyl-(C2-C5)heteroaryl, C(O)R3, C(O)OR4, (C1-C8)alkyl-N(R6)2, (C1-C8)alkyl-OR5, (C1-C8)alkyl-C(O)ORS, C(S)NHR3, or (C1-C8)alkyl-O(CO)R5;
R2 is H or (C1-C8)alkyl; and
R3 is (C1-C8)alkyl, (C3-C7)cycloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, (C0-C4)alkyl-(C1-C6)heterocycloalkyl, (C0-C4)alkyl-(C2-C5)heteroaryl, (C5-C8)alkyl-N(R6)2; (C0-C8)alkyl-NH—C(O)O—R5; (C1-C8)alkyl-OR5, (C1-C8)alkyl-C(O)OR5, (C1-C8)alkyl-O(CO)R5, or C(O)OR5; and the other variables have the same definitions.
In other specific compounds of formula II, R2 is H or (C1-C4)alkyl.
In other specific compounds of formula II, R1 is (C1-C8)alkyl or benzyl.
In other specific compounds of formula II, R1 is H, (C1-C8)alkyl, benzyl, CH2OCH3, CH2CH2OCH3, or
In another embodiment of the compounds of formula II, R1 is
wherein Q is O or S, and each occurrence of R7 is independently H, (C1-C8)alkyl, benzyl, CH2OCH3, or CH2CH2OCH3.
In other specific compounds of formula II, R1 is C(O)R3.
In other specific compounds of formula II, R3 is (C0-C4)alkyl-(C2-C5)heteroaryl, (C1-C8)alkyl, aryl, or (C0-C4)alkyl-OR5.
In other specific compounds of formula II, heteroaryl is pyridyl, furyl, or thienyl.
In other specific compounds of formula II, R1 is C(O)OR4.
In other specific compounds of formula II, the H of C(O)NHC(O) can be replaced with (C1-C4)alkyl, aryl, or benzyl.
Still other specific immunomodulatory compounds of the invention belong to a class of isoindole-imides disclosed in U.S. patent application Ser. No. 09/781,179, International Publication No. WO 98/54170, and U.S. Pat. No. 6,395,754, each of which are incorporated herein by reference. Representative compounds are of formula III:
and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:
one of X and Y is C═O and the other is CH2 or C═O;
R is H or CH2OCOR′;
(i) each of R1, R2, R3, or R4, independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3, or R4 is nitro or —NHR5 and the remaining of R1, R2, R3, or R4 are hydrogen;
R5 is hydrogen or alkyl of 1 to 8 carbons
R6 hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro;
R′ is R7—CHR10—N(R8R9);
R7 is m-phenylene or p-phenylene or —(CnH2n)— in which n has a value of 0 to 4;
each of R8 and R9 taken independently of the other is hydrogen or alkyl of 1 to 8 carbon atoms, or R8 and R9 taken together are tetramethylene, pentamethylene, hexamethylene, or —CH2CH2[X]X1CH2CH2— in which [X]X1 is —O—, —S—, or —NH—;
R10 is hydrogen, alkyl of to 8 carbon atoms, or phenyl; and
* represents a chiral-carbon center.
The most preferred immunomodulatory compounds of the invention are 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione and 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. The compounds can be obtained via standard, synthetic methods (see e.g., U.S. Pat. No. 5,635,517, incorporated herein by reference). The compounds are available from Celgene Corporation, Warren, N.J. 4-(Amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (ACTIMID™) has the following chemical structure:
The compound 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (REVIMID™) has the following chemical structure:
Compounds of the invention can either be commercially purchased or prepared according to the methods described in the patents or patent publications disclosed herein. Further, optically pure compounds can be asymmetrically synthesized or resolved using known resolving agents or chiral columns as well as other standard synthetic organic chemistry techniques.
As used herein and unless otherwise indicated, the term “pharmaceutically acceptable salt” encompasses non-toxic acid and base addition salts of the compound to which the term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases know in the art, which include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid, and the like.
Compounds that are acidic in nature are capable of forming salts with various pharmaceutically acceptable bases. The bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds are those that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations such as, but not limited to, alkali metal or alkaline earth metal salts and the calcium, magnesium, sodium or potassium salts in particular. Suitable organic bases include, but are not limited to, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine, and procaine.
As used herein and unless otherwise indicated, the term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, derivatives of immunomodulatory compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of immunomodulatory compounds of the invention that comprise —NO, —NO2, —ONO, or —ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described in 1 Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York 1985).
As used herein and unless otherwise indicated, the terms “biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzable carbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide”, “biohydrolyzable phosphate” mean an amide, ester, carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologically inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (such as acetoxylmethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyl-oxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylamino alkyl esters (such as acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
Various immunomodulatory compounds of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers or mixtures of diastereomers. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular immunomodulatory compounds of the invention may be used in methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).
As used herein and unless otherwise indicated, the term “stereomerically pure” means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. As used herein and unless otherwise indicated, the term “stereomerically enriched” means a composition that comprises greater than about 60% by weight of one stereoisomer of a compound, preferably greater than about 70% by weight, more preferably greater than about 80% by weight of one stereoisomer of a compound. As used herein and unless otherwise indicated, the term “enantiomerically pure” means a stereomerically pure composition of a compound having one chiral center. Similarly, the term “stereomerically enriched” means a stereomerically enriched composition of a compound having one chiral center.
It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
Immunomodulatory compounds can be combined with other pharmacologically active compounds (“second active agents”) in methods and compositions of the invention. It is believed that certain combinations work synergistically in the treatment of particular types of cancer and certain diseases and conditions associated with, or characterized by, undesired angiogenesis. Immunomodulatory compounds can also work to alleviate adverse effects associated with certain second active agents, and some second active agents can be used to alleviate adverse effects associated with immunomodulatory compounds.
One or more second active ingredients or agents can be used in the methods and compositions of the invention together with an immunomodulatory compound. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).
Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Typical large molecule active agents are biological molecules, such as naturally occurring or artificially made proteins. Proteins that are particularly useful in this invention include proteins that stimulate the survival and/or proliferation of hematopoietic precursor cells and immunologically active poietic cells in vitro or in vivo. Others stimulate the division and differentiation of committed erythroid progenitors in cells in vitro or in vivo. Particular proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18; interferons, such as interferon alfa-2a, interferon alfa-2b, interferon alfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO.
Particular proteins that can be used in the methods and compositions of the invention include, but are not limited to: filgrastim, which is sold in the United States under the trade name Neupogen® (Amgen, Thousand Oaks, Calif.); sargramostim, which is sold in the United States under the trade name Leukine® (Immunex, Seattle, Wash.); and recombinant EPO, which is sold in the United States under the trade name Epogen® (Amgen, Thousand Oaks, Calif.).
Recombinant and mutated forms of GM-CSF can be prepared as described in U.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; all of which are incorporated herein by reference. Recombinant and mutated forms of G-CSF can be prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755; all of which are incorporated herein by reference.
This invention encompasses the use of native, naturally occurring, and recombinant proteins. The invention further encompasses mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit, in vivo, at least some of the pharmacological activity of the proteins upon which they are based. Examples of mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the proteins. Also encompassed by the term “mutants” are proteins that lack carbohydrate moieties normally present in their naturally occurring forms (e.g., nonglycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to the protein or active portion of the protein of interest. See, e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. Methods 248:91-101 (2001).
Antibodies that can be used in combination with compounds of the invention include monoclonal and polyclonal antibodies. Examples of antibodies include, but are not limited to, trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (Avastin™), pertuzumab (Omnitarg™), tositumomab (Bexxar®), edrecolomab (Panorex®), and G250. Compounds of the invention can also be combined with, or used in combination with, anti-TNF-αantibodies.
Large molecule active agents may be administered in the form of anti-cancer vaccines. For example, vaccines that secrete, or cause the secretion of, cytokines such as IL-2, G-CSF, and GM-CSF can be used in the methods, pharmaceutical compositions, and kits of the invention. See, e.g., Emens, L. A., et al., Curr. Opinion Mol. Ther. 3(1):77-84 (2001).
In one embodiment of the invention, the large molecule active agent reduces, eliminates, or prevents an adverse effect associated with the administration of an immunomodulatory compound. Depending on the particular immunomodulatory compound and the disease or disorder begin treated, adverse effects can include, but are not limited to, drowsiness and somnolence, dizziness and orthostatic hypotension, neutropenia, infections that result from neutropenia, increased HIV-viral load, bradycardia, Stevens-Johnson Syndrome and toxic epidermal necrolysis, and seizures (e.g., grand mal convulsions). A specific adverse effect is neutropenia.
Second active agents that are small molecules can also be used to alleviate adverse effects associated with the administration of an immunomodulatory compound. However, like some large molecules, many are believed to be capable of providing a synergistic effect when administered with (e.g., before, after or simultaneously) an immunomodulatory compound. Examples of small molecule second active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids.
Examples of anti-cancer agents include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.
Other anti-cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib (e.g., Gleevec®), imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense®); O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
Specific second active agents include, but are not limited to, oblimersen (Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt®), sulindac, and etoposide.
Methods of this invention encompass methods of treating, preventing and/or managing various types of cancer and diseases and disorders associated with, or characterized by, undesired angiogenesis. As used herein, unless otherwise specified, the term “treating” refers to the administration of a compound of the invention or other additional active agent after the onset of symptoms of the particular disease or disorder. As used herein, unless otherwise specified, the term “preventing” refers to the administration prior to the onset of symptoms, particularly to patients at risk of cancer, and other diseases and disorders associated with, or characterized by, undesired angiogenesis. The term “prevention” includes the inhibition of a symptom of the particular disease or disorder. Patients with familial history of cancer and diseases and disorders associated with, or characterized by, undesired angiogenesis are preferred candidates for preventive regimens. As used herein and unless otherwise indicated, the term “managing” encompasses preventing the recurrence of the particular disease or disorder in a patient who had suffered from it, and/or lengthening the time a patient who had suffered from the disease or disorder remains in remission.
As used herein, the term “cancer” includes, but is not limited to, solid tumors and blood born tumors. The term “cancer” refers to disease of skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone or blood, brain, breast, cervix, chest, colon, endrometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus. Specific cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastase, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant giolma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma. In a specific embodiment, the cancer is metastatic. In another embodiment, the cancer is refractory or resistance to chemotherapy or radiation; in particular, refractory to thalidomide.
As used herein to refer to diseases and conditions other than cancer, the terms “diseases or disorders associated with, or characterized by, undesired angiogenesis”, “diseases or disorders associated with undesired angiogenesis”, and “diseases or disorders characterized by undesired angiogenesis” refer to diseases, disorders and conditions that are caused, mediated or attended by undesired, unwanted or uncontrolled angiogenesis, including, but not limited to, inflammatory diseases, autoimmune diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, and retina neovascular diseases.
Examples of such diseases or disorders associated with undesired angiogenesis include, but are not limited to, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, proliferative vitreoretinopathy, trachoma, myopia, optic pits, epidemnic keratoconjunctivitis, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis, syphilis, lipid degeneration, bacterial ulcer, fungal ulcer, Herpes simplex infection, Herpes zoster infection, protozoan infection, Kaposi sarcoma, Mooren ulcer, Terrien's marginal degeneration, mariginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, Wegeners sarcoidosis, Scleritis, Steven's Johnson disease, periphigoid radial keratotomy, sickle cell anemia, sarcoid, pseudoxanthoma elasticum, Pagets disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis, chronic vitritis, Lyme's disease, Eales disease, Behcet's disease, retinitis, choroiditis, presumed ocular histoplasmosis, Bests disease, Stargarts disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, rubeosis, sarcodisis, sclerosis, soriatis, psoriasis, primary sclerosing cholangitis, proctitis, primary biliary srosis, idiopathic pulmonary fibrosis, and alcoholic hepatitis.
In specific embodiments of the invention, diseases or disorders associated with undesired angiogenesis do not include congestive heart failure, cardiomyopathy, pulmonary edema, endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft rejection, myocardial infarction, HIV, hepatitis, adult respiratory distress syndrome, bone-resorption disease, chronic obstructive pulmonary diseases, chronic pulmonary inflammatory disease, dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, meningitis, psoriasis, fibrotic disease, cachexia, graft rejection, rheumatoid spondylitis, osteoporosis, Crohn's disease, ulcerative colitis, inflammatory-bowel disease, multiple sclerosis, systemic lupus erythrematosus, erythema nodosum leprosum in leprosy, radiation damage, asthma, hyperoxic alveolar injury, malaria, mycobacterial infection, and opportunistic infections resulting from HIV.
This invention encompasses methods of treating patients who have been previously treated for cancer or diseases or disorders associated with, or characterized by, undesired angiogenesis, but are non-responsive to standard therapies, as well as those who have not previously been treated. The invention also encompasses methods of treating patients regardless of patient's age, although some diseases or disorders are more common in certain age groups. The invention further encompasses methods of treating patients who have undergone surgery in an attempt to treat the disease or condition at issue, as well as those who have not. Because patients with cancer and diseases and disorders characterized by undesired angiogenesis have heterogenous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his/her prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual patient with cancer and other diseases or disorders.
Methods encompassed by this invention comprise administering one or more immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, to a patient (e.g., a human) suffering, or likely to suffer, from cancer or a disease or disorder mediated by undesired angiogenesis.
In one embodiment of the invention, an immunomodulatory compound of the invention can be administered orally and in single or divided daily doses in an amount of from about 0.10 to about 150 mg/day. In a particular embodiment, 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (Actimid™) may be administered in an amount of from about 0.1 to about 1 mg per day, or alternatively from about 0.1 to about 5 mg every other day. In a preferred embodiment, 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl-piperidine-2,6-dione (Revimid™) may be administered in an amount of from about 5 to 25 mg per day, or alternatively from about 10 to about 50 mg every other day.
In a specific embodiment, 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (Actimid™) may be administered in an amount of about 1, 2, or 5 mg per day to patients with relapsed multiple myeloma. In a particular embodiment, 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Revimid™) may be administered initially in an amount of 5 mg/day and the dose can be escalated every week to 10, 20, 25, 30 and 50 mg/day. In a specific embodiment, Revimid™ can be administered in an amount of up to about 30 mg/day to patients with solid tumor. In a particular embodiment, Revimid™ can be administered in an amount of up to about 40 mg/day to patients with glioma.
5.3.1 Combination Therapy with a Second Active Agent
Specific methods of the invention comprise administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in combination with one or more second active agents, and/or in combination with radiation therapy, blood transfusions, or surgery. Examples of immunomodulatory compounds of the invention are disclosed herein (see, e.g., section 5.1). Examples of second active agents are also disclosed herein (see, e.g., section 5.2).
Administration of the immunomodulatory compounds and the second active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated. A preferred route of administration for an immunomodulatory compound of the invention is orally. Preferred routes of administration for the second active agents or ingredients of the invention are known to those of ordinary skill in the art. See, e.g., Physicians' Desk Reference, 1755-1760 (56th ed., 2002).
In one embodiment of the invention, the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount(s) of immunomodulatory compounds of the invention and any optional additional active agents concurrently administered to the patient. In a particular embodiment, the second active agent is oblimersen (Genasense®), GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitor, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or a combination thereof.
In a particular embodiment, GM-CSF, G-CSF or EPO is administered subcutaneously during about five days in a four or six week cycle in an amount of from about 1 to about 750 mg/m2/day, preferably in an amount of from about 25 to about 500 mg/m2/day, more preferably in an amount of from about 50 to about 250 mg/m2/day, and most preferably in an amount of from about 50 to about 200 mg/m2/day. In a certain embodiment, GM-C SF may be administered in an amount of from about 60 to about 500 mcg/m2 intravenously over 2 hours, or from about 5 to about 12 mcg/m2/day subcutaneously. In a specific embodiment, G-CSF may be administered subcutaneously in an amount of about 1 mcg/kg/day initially and can be adjusted depending on rise of total granulocyte counts. The maintenance dose of G-CSF may be administered in an amount of about 300 (in smaller patients) or 480 mcg subcutaneously. In a certain embodiment, EPO may be administered subcutaneously in an amount of 10,000 Unit 3 times per week.
In another embodiment, Revimid™ in an amount of about 25 mg/d and dacarbazine in an amount of about from 200 to 1,000 mg/m2/d are administered to patients with metastatic malignant melanoma. In a specific embodiment, Revimid™ is administered in an amount of from about 5 to about 25 mg/d to patients with metastatic malignant melanoma whose disease has progressed on treatment with dacarbazine, IL-2 or IFN. In a specific embodiment, Revimid™ is administered to patients with relapsed or refractory multiple myeloma in an amount of about 15 mg/d twice a day or about 30 mg/d four times a day in a combination with dexamethasone.
In another embodiment, an immunomodulatory compound is administered with melphalan and dexamethasone to patients with amyloidosis. In a specific embodiment, an immunomodulatory compound of the invention and steroids can be administered to patients with amyloidosis.
In another embodiment, an immunomodulatory compound is administered with gemcitabine and cisplatinum to patients with locally advanced or metastatic transitional cell bladder cancer.
In another embodiment, an immunomodulatory compound is administered in combination with a second active ingredient as follows: temozolomide to pediatric patients with relapsed or progressive brain tumors or recurrent neuroblastoma; celecoxib, etoposide and cyclophosphamide for relapsed or progressive CNS cancer; temodar to patients with recurrent or progressive meningioma, malignant meningioma, hemangiopericytoma, multiple brain metastases, relapased brain tumors, or newly diagnosed glioblastoma multiforms; irinotecan to patients with recurrent glioblastoma; carboplatin to pediatric patients with brain stem glioma; procarbazine to pediatric patients with progressive malignant gliomas; cyclophosphamide to patients with poor prognosis malignant brain tumors, newly diagnosed or recurrent glioblastoma multiforms; Gliadel® for high grade recurrent malignant gliomas; temozolomide and tamoxifen for anaplastic astrocytoma; or topotecan for gliomas, glioblastoma, anaplastic astrocytoma or anaplastic oligodendroglioma.
In another embodiment, an immunomodulatory compound is administered with methotrexate and cyclophosphamide to patients with metastatic breast cancer.
In another embodiment, an immunomodulatory compound is administered with temozolomide to patients with neuroendocrine tumors.
In another embodiment, an immunomodulatory compound is administered with gemcitabine to patients with recurrent or metastatic head or neck cancer. In another embodiment, an immunomodulatory compound is administered with gemcitabine to patients with pancreatic cancer.
In another embodiment, an immunomodulatory compound is administered to patients with colon cancer in combination with Arisa®, taxol and/or taxotere.
In another embodiment, an immunomodulatory compound is administered with capecitabine to patients with refractory colorectal cancer or patients who fail first line therapy or have poor performance in colon or rectal adenocarcinoma.
In another embodiment, an immunomodulatory compound is administered in combination with fluorouracil, leucovorin, and irinotecan to patients with Dukes C & D colorectal cancer or to patients who have been previously treated for metastatic colorectal cancer.
In another embodiment, an immunomodulatory compound is administered to patients with refractory colorectal cancer in combination with capecitabine, xeloda, and/or CPT-11.
In another embodiment, an immunomodulatory compound of the invention is administered with capecitabine and irinotecan to patients with refractory colorectal cancer or to patients with unresectable or metastatic colorectal carcinoma.
In another embodiment, an immunomodulatory compound is administered alone or in combination with interferon alpha or capecitabine to patients with unresectable or metastatic hepatocellular carcinoma; or with cisplatin and thiotepa to patients with primary or metastatic liver cancer.
In another embodiment, an immunomodulatory compound is administered in combination with pegylated interferon alpha to patients with Kaposi's sarcoma.
In another embodiment, an immunomodulatory compound is administered in combination with fludarabine, carboplatin, and/or topotecan to patients with refractory or relapsed or high-risk acuted myelogenous leukemia.
In another embodiment, an immunomodulatory compound is administered in combination with liposomal daunorubicin, topotecan and/or cytarabine to patients with unfavorable karotype acute myeloblastic leukemia.
In another embodiment, an immunomodulatory compound is administered in combination with gemcitabine and irinotecan to patients with non-small cell lung cancer. In one embodiment, an immunomodulatory compound is administered in combination with carboplatin and irinotecan to patients with non-small cell lung cancer. In one embodiment, an immunomodulatory compound is administered with doxetaxol to patients with non-small cell lung cancer who have been previously treated with carbo/VP 16 and radiotherapy.
In another embodiment, an immunomodulatory compound is administered in combination with carboplatin and/or taxotere, or in combination with carboplatin, pacilitaxel and/or thoracic radiotherapy to patients with non-small cell lung cancer. In a specific embodiment, an immunomodulatory compound is administered in combination with taxotere to patients with stage IIIB or IV non-small cell lung cancer.
In another embodiment, an immunomodulatory compound of the invention is administered in combination with oblimersen (Genasense®) to patients with small cell lung cancer.
In another embodiment, an immunomodulatory compound is administered alone or in combination with a second active ingredient such as vinblastine or fludarabine to patients with various types of lymphoma, including, but not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low grade follicular lymphoma.
In another embodiment, an immunomodulatory compound is administered in combination with taxotere, IL-2, IFN, GM-CSF, and/or dacarbazine to patients with various types or stages of melanoma.
In another embodiment, an immunomodulatory compound is administered alone or in combination with vinorelbine to patients with malignant mesothelioma, or stage IIIB non-small cell lung cancer with pleural implants or malignant pleural effusion mesothelioma syndrome.
In another embodiment, an immunomodulatory compound is administered to patients with various types or stages of multiple myeloma in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan, cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, or a combination thereof.
In another embodiment, an immunomodulatory compound is administered to patients with relapsed or refractory multiple myeloma in combination with doxorubicin (Doxil®), vincristine and/or dexamethasone (Decadron®).
In another embodiment, an immunomodulatory compound is administered to patients with various types or stages of ovarian cancer such as peritoneal carcinoma, papillary serous carcinoma, refractory ovarian cancer or recurrent ovarian cancer, in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or a combination thereof.
In another embodiment, an immunomodulatory compound is administered to patients with various types or stages of prostate cancer, in combination with xeloda, 5 FU/LV, gemcitabine, irinotecan plus gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, or a combination thereof.
In another embodiment, an immunomodulatory compound is administered to patients with various types or stages of renal cell cancer, in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination thereof.
In another embodiment, an immunomodulatory compound is administered to patients with various types or stages of gynecologic, uterus or soft tissue sarcoma cancer in combination with IFN, a COX-2 inhibitor such as Celebrex®, and/or sulindac.
In another embodiment, an immunomodulatory compound is administered to patients with various types or stages of solid tumors in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
In another embodiment, an immunomodulatory compound is administered to patients with scleroderma or cutaneous vasculitis in combination with celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.
This invention also encompasses a method of increasing the dosage of an anti-cancer drug or agent that can be safely and effectively administered to a patient, which comprises administering to a patient (e.g., a human) an immunomodulatory compound of the invention, or a pharmaceutically acceptable derivative, salt, solvate, clathrate, hydrate, or prodrug thereof. Patients that can benefit by this method are those likely to suffer from an adverse effect associated with anti-cancer drugs for treating a specific cancer of the skin, subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas, adrenal, kidney, prostate, breast, colorectal, or combinations thereof. The administration of an immunomodulatory compound of the invention alleviates or reduces adverse effects which are of such severity that it would otherwise limit the amount of anti-cancer drug.
In one embodiment, an immunomodulatory compound of the invention can be administered orally and daily in an amount of from about 0.1 to about 150 mg, and preferably from about 1 to about 50 mg, more preferably from about 2 to about 25 mg prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient. In a particular embodiment, an immunomodulatory compound of the invention is administered in combination with specific agents such as heparin, aspirin, coumadin, or G-CSF to avoid adverse effects that are associated with anti-cancer drugs such as but not limited to neutropenia or thrombocytopenia.
In one embodiment, an immunomodulatory compound of the invention can be administered to patients with diseases and disorders associated with, or characterized by, undesired angiogenesis in combination with additional active ingredients including but not limited to anti-cancer drugs, anti-inflammatories, antihistamines, antibiotics, and steroids.
In another embodiment, this invention encompasses a method of treating, preventing and/or managing cancer, which comprises administering an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in conjunction with (e.g. before, during, or after) conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug based therapy presently used to treat, prevent or manage cancer. The combined use of the immunomodulatory compounds of the invention and conventional therapy may provide a unique treatment regimen that is unexpectedly effective in certain patients. Without being limited by theory, it is believed that immunomodulatory compounds of the invention may provide additive or synergistic effects when given concurrently with conventional therapy.
As discussed elsewhere herein, the invention encompasses a method of reducing, treating and/or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. One or more immunomodulatory compounds of the invention and other active ingredient can be administered to a patient prior to, during, or after the occurrence of the adverse effect associated with conventional therapy.
In one embodiment, an immunomodulatory compound of the invention can be administered in an amount of from about 0.1 to about 150 mg, and preferably from about 1 to about 25 mg, more preferably from about 2 to about 10 mg orally and daily alone, or in combination with a second active agent disclosed herein (see, e.g., section 5.2), prior to, during, or after the use of conventional therapy.
In a specific embodiment of this method, an immunomodulatory compound of the invention and doxetaxol are administered to patients with non-small cell lung cancer who were previously treated with carbo/VP 16 and radiotherapy.
5.3.2 Use with Transplantation Therapy
Compounds of the invention can be used to reduce the risk of Graft Versus Host Disease (GVHD). Therefore, the invention encompasses a method of treating, preventing and/or managing cancer, which comprises administering the immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in conjunction with transplantation therapy.
As those of ordinary skill in the art are aware, the treatment of cancer is often based on the stages and mechanism of the disease. For example, as inevitable leukemic transformation develops in certain stages of cancer, transplantation of peripheral blood stem cells, hematopoietic stem cell preparation or bone marrow may be necessary. The combined use of the immunomodulatory compound of the invention and transplantation therapy provides a unique and unexpected synergism. In particular, an immunomodulatory compound of the invention exhibits immunomodulatory activity that may provide additive or synergistic effects when given concurrently with transplantation therapy in patients with cancer.
An immunomodulatory compound of the invention can work in combination with transplantation therapy reducing complications associated with the invasive procedure of transplantation and risk of GVHD. This invention encompasses a method of treating, preventing and/or managing cancer which comprises administering to a patient (e.g., a human) an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, before, during, or after the transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow. Examples of stem cells suitable for use in the methods of the invention are disclosed in U.S. provisional patent application No. 60/372,348, filed Apr. 12, 2002 by R. Hariri et al., the entirety of which is incorporated herein by reference.
In one embodiment of this method, an immunomodulatory compound of the invention is administered to patients with multiple myeloma before, during, or after the transplantation of autologous peripheral blood progenitor cell.
In another embodiment, an immunomodulatory compound is administered to patients with relapsing multiple myeloma after the stem cell transplantation.
In another embodiment, an immunomodulatory compound and prednisone are administered as maintenance therapy to patients with multiple myeloma following the transplantation of autologous stem cell.
In another embodiment, an immunomodulatory compound and dexamethasone are administered as salvage therapy for low risk post transplantation to patients with multiple myeloma.
In another embodiment, an immunomodulatory compound and dexamethasone are administered as maintenance therapy to patients with multiple myeloma following the transplantation of autologous bone marrow.
In another embodiment, an immunomodulatory compound is administered following the administration of high dose of melphalan and the transplantation of autologous stem cell to patients with chemotherapy responsive multiple myeloma.
In another embodiment, an immunomodulatory compound and PEG INTRO-A are administered as maintenance therapy to patients with multiple myeloma following the transplantation of autologous CD34-selected peripheral stem cell.
In another embodiment, an immunomodulatory compound is administered with post transplant consolidation chemotherapy to patients with newly diagnosed multiple myeloma to evaluate anti-angiogenesis.
In another embodiment, an immunomodulatory compound and dexamethasone are administered as maintenance therapy after DCEP consolidation, following the treatment with high dose of melphalan and the transplantation of peripheral blood stem cell to 65 years of age or older patients with multiple myeloma.
5.3.3 Cycling Therapy
In certain embodiments, the prophylactic or therapeutic agents of the invention are cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
Consequently, in one specific embodiment of the invention, an immunomodulatory compound of the invention is administered daily in a single or divided doses in a four to six week cycle with a rest period of about a week or two weeks. The invention further allows the frequency, number, and length of dosing cycles to be increased. Thus, another specific embodiment of the invention encompasses the administration of an immunomodulatory compound of the invention for more cycles than are typical when it is administered alone. In yet another specific embodiment of the invention, an immunomodulatory compound of the invention is administered for a greater number of cycles that would typically cause dose-limiting toxicity in a patient to whom a second active ingredient is not also being administered.
In one embodiment, an immunomodulatory compound of the invention is administered daily and continuously for three or four weeks at a dose of from about 0.1 to about 150 mg/d followed by a break of one or two weeks. Actimid™ is preferably administered daily and continuously at an initial dose of 0.1 to 5 mg/d with dose escalation (every week) by 1 to 10 mg/d to a maximum dose of 50 mg/d for as long as therapy is tolerated. In a particular embodiment, Revimid™ is administered in an amount of about 5, 10, or 25 mg/day, preferably in an amount of about 10 mg/day for three to four weeks, followed by one week or two weeks of rest in a four or six week cycle.
In one embodiment of the invention, an immunomodulatory compound of the invention and a second active ingredient are administered orally, with administration of an immunomodulatory compound of the invention occurring 30 to 60 minutes prior to a second active ingredient, during a cycle of four to six weeks. In another embodiment of the invention, the combination of an immunomodulatory compound of the invention and a second active ingredient is administered by intravenous infusion over about 90 minutes every cycle. In a specific embodiment, one cycle comprises the administration of from about 10 to about 25 mg/day of Revimid™ and from about 50 to about 200 mg/m2/day of a second active ingredient daily for three to four weeks and then one or two weeks of rest. In another specific embodiment, each cycle comprises the administration of from about 5 to about 10 mg/day of Actimid™ and from about 50 to about 200 mg/m2/day of a second active ingredient for 3 to 4 weeks followed by one or two weeks of rest. Typically, the number of cycles during which the combinatorial treatment is administered to a patient will be from about one to about 24 cycles, more typically from about two to about 16 cycles, and even more typically from about four to about three cycles.
Pharmaceutical compositions can be used in the preparation of individual, single unit dosage forms. Pharmaceutical compositions and dosage forms of the invention comprise an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Pharmaceutical compositions and dosage forms of the invention can further comprise one or more excipients.
Pharmaceutical compositions and dosage forms of the invention can also comprise one or more additional active ingredients. Consequently, pharmaceutical compositions and dosage forms of the invention comprise the active ingredients disclosed herein (e.g., an immunomodulatory compound and a second active agent). Examples of optional second, or additional, active ingredients are disclosed herein (see, e.g., section 5.2).
Single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal or transcutaneous administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
The composition, shape, and type of dosage forms of the invention will typically vary depending on their use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease. These and other ways in which specific dosage forms encompassed by this invention will vary from one another will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).
Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, this invention encompasses pharmaceutical compositions and dosage forms that contain little, if any, lactose other mono- or di-saccharides. As used herein, the term “lactose-free” means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
Lactose-free compositions of the invention can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Preferred lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
The invention further encompasses pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as “stabilizers”, include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients. However, typical dosage forms of the invention comprise an immunomodulatory compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in an amount of from about 0.10 to about 150 mg. Typical dosage forms comprise an immunomodulatory compound of the invention or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150 or 200 mg. In a particular embodiment, a preferred dosage form comprises 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (Actimid™) in an amount of about 1, 2, 5, 10, 25 or 50 mg. In a specific embodiment, a preferred dosage form comprises 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Revimid™) in an amount of about 5, 10, 25 or 50 mg. Typical dosage forms comprise the second active ingredient in an amount of 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. Of course, the specific amount of the anti-cancer drug will depend on the specific agent used, the type of cancer being treated or managed, and the amount(s) of an immunomodulatory compound of the invention and any optional additional active agents concurrently administered to the patient.
Pharmaceutical compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).
Typical oral dosage forms of the invention are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
Examples of excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM.
Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.
Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
A preferred solid oral dosage form of the invention comprises an immunomodulatory compound of the invention, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.
Active ingredients of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.
Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms of the invention. For example, cyclodextrin and its derivatives can be used to increase the solubility of an immunomodulatory compound of the invention and its derivatives. See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein by reference.
Topical and mucosal dosage forms of the invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.
Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 1990).
The pH of a pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
Typically, active ingredients of the invention are preferably not administered to a patient at the same time or by the same route of administration. This invention therefore encompasses kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.
A typical kit of the invention comprises a dosage form of an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof. Kits encompassed by this invention can further comprise additional active ingredients such as oblimersen (Genasense®), melphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitor, pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13 cis-retinoic acid, or a pharmacologically active mutant or derivative thereof, or a combination thereof. Examples of the additional active ingredients include, but are not limited to, those disclosed herein (see, e.g., section 5.2).
Kits of the invention can further comprise devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.
Kits of the invention can further comprise cells or blood for transplantation as well as pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
Certain embodiments of the invention are illustrated by the following non-limiting examples.
A series of non-clinical pharmacology and toxicology studies have been performed to support the clinical evaluation of an immunomodulatory compound of the invention in human subjects. These studies were performed in accordance with internationally recognized guidelines for study design and in compliance with the requirements of Good Laboratory Practice (GLP), unless otherwise noted.
Inhibition of TNF-α production following LPS-stimulation of human PBMC and human whole blood by 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (Actimid™), 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione and thalidomide (Revimid™) was investigated in vitro (Muller et al., Bioorg. Med. Chem. Lett. 9:1625-1630, 1999). The IC50's of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione for inhibiting production of TNF-α following LPS-stimulation of PBMC and human whole blood were ˜24 nM (6.55 ng/mL) and ˜25 nM (6.83 ng/mL), respectively. In vitro studies suggest a pharmacological activity profile for 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that is similar to, but at least 200 times more potent than, thalidomide. In vitro studies have also demonstrated that concentrations of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione of 2.73 to 27.3 ng/mL (0.01 to 0.1 μM) achieved 50% inhibition of the proliferation of MM.IS and Hs Sultan cells.
The IC50's of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for inhibiting production of TNF-α following LPS-stimulation of PBMC and human whole blood were ˜100 nM (25.9 ng/mL) and ˜480 nM (103.6 ng/mL), respectively. Thalidomide, in contrast, had an IC50 of ˜194 μM (50.2 μg/mL) for inhibiting production of TNF-α following LPS-stimulation of PBMC. In vitro studies suggest a pharmacological activity profile for 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione that is similar to, but 50 to 2000 times more potent than, thalidomide. It has been shown that the compound is approximately 50-100 times more potent than thalidomide in stimulating the proliferation of T-cells following primary induction by T-cell receptor (TCR) activation. 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is also approximately 50 to 100 times more potent than thalidomide in augmenting the production of IL-2 and IFN-γ following TCR activation of PBMC (IL-2) or T-cells (IFN-γ). In addition, 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione exhibited dose-dependent inhibition of LPS-stimulated production of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 by PBMC while it increased production of the anti-inflammatory cytokine IL-10.
The ability of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Revimid™) and thalidomide for comparison to effect the proliferation of MM cell lines has been investigated in an in vitro study. Uptake [3H]-thymidine by different MM cell lines (MM.1S, Hs Sultan, U266 and RPMI-8226) was measured as an indicator of cell proliferation. Cells were incubated in the presence of compounds for 48 hours; [3H]-thymidine was included for the last 8 hours of the incubation period. Addition of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione to MM.1S and Hs Sultan cells resulted in 50% inhibition of cell proliferation at concentrations of 0.4 μm and 1 μm, respectively. In contrast, addition of thalidomide at concentrations up to 100 μm resulted in only 15% and 20% inhibition of cell proliferation in MM.1S and Hs Sultan cells, respectively. These data are summarized in FIG. 1 .
The effects of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Revimid™) on cardiovascular and respiratory function are investigated in anesthetized dogs. Two groups of Beagle dogs (2/sex/group) are used. One group receives three doses of vehicle only and the other receives three ascending doses of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (2, 10, and 20 mg/kg). In all cases, doses of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione or vehicle are successively administered via infusion through the jugular vein separated by intervals of at least 30 minutes.
The cardiovascular and respiratory changes induced by 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione are minimal at all doses when compared to the vehicle control group. The only statistically significant difference between the vehicle and treatment groups is a small increase in arterial blood pressure (from 94 mmHg to 101 mmHg) following administration of the low dose of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. This effect lasts approximately 15 minutes and is not seen at higher doses. Deviations in femoral blood flow, respiratory parameters, and Qtc interval are common to both the control and treated groups and are not considered treatment-related.
In a specific embodiment, an immunomodulatory compound of the invention are cyclically administered to patients with cancer. Cycling therapy involves the administration of a first agent for a period of time, followed by a rest for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
In a specific embodiment, prophylactic or therapeutic agents are administered in a cycle of about 4 to 6 weeks, about once or twice every day. One cycle can comprise the administration of a therapeutic on prophylactic agent for three to four weeks and at least a week or two weeks of rest. The number of cycles administered is from about one to about 24 cycles, more typically from about two to about 16 cycles, and more typically from about four to about eight cycles.
For example, in a cycle of four weeks, on day 1, the administration of 25 mg/d of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is started. On day 22, the administration of the compound is stopped for a week of rest. On day 29, the administration of 25 mg/d 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidin-2,6-dione is begun.
6.5.1 Treatment of Relapsed Multiple Myeloma
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (Actimid™) was administered to patients with relapsed/refractory multiple myeloma. The study was conducted in compliance with Good Clinical Practices. Patients were at least 18 years old, had been diagnosed with multiple myeloma (with paraprotein in serum and/or urine), and were considered refractory to treatment after at least two cycles of treatment, or have relapsed after two cycles of treatment.
Patients who have progressive disease, according to the Southwest Oncology Group (SWOG) criteria, on their prior regimen are considered treatment refractory. Relapse following remission is defined as >25% increase in M component from baseline levels; reappearance of the M paraprotein that had previously disappeared; or a definite increase in the size and number of lytic bone lesions recognized on radiographs. Patients may have had prior therapy with thalidomide, provided they were able to tolerate the treatment. A Zubrod performance status of 0 to 2 is required for all patients.
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione is administered to patients at doses of 1, 2, 5, or 10 mg/day for up to four weeks; at each dose level, three patients are initially enrolled. Dosing occurs at approximately the same time each morning; all doses are administered in the fasted state (no eating for at least two hours prior to dosing and two hours after dosing). 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione doses are administered in an ascending fashion such that patients in the first cohort receive the lowest dose of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (1 mg/day) and escalation to the next higher dose level occurs only following the establishment of safety and tolerability at the current dose. If one out of three patients at any dose level experience dose limiting toxicity (DLT), three additional patients are enrolled at that dose. If none of the three additional patients experience DLT, escalation to the next dose level occurs; dose escalations continue in a similar fashion until the MTD is established or the maximum daily dose (10 mg/day) is attained. However, if one of the three additional patients enrolled experiences DLT, the MTD has been reached. If two or more of the three additional patients enrolled experience DLT, the MTD is judged to have been exceeded and three additional patients are enrolled at the preceding dose level to confirm the MTD. Once the MTD has been identified, four additional patients are enrolled at that dose level so that a total of 10 patients is treated at the MTD.
Blood sampling for analysis of pharmacokinetic parameters is performed on Days 1 and 28 according to the following sampling schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose. An additional blood sample is collected at each weekly visit for the determination of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione levels. Total urine collections are also made with urine pooled according to the following time intervals post-dose: 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours. Safety assessments are made by monitoring adverse events, vital signs, ECGs, clinical laboratory evaluations (blood chemistry, hematology, lymphocyte phenotyping, and urinalysis), and physical examination at specific times during the study.
Results of interim pharmacokinetic analyses obtained following single- and multiple-dose administration of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione to multiple myeloma patients are presented below in Tables 1 and 2. These data show that 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione was steadily absorbed at all dose levels in relapsed multiple myeloma patients. Maximum plasma concentrations occurred at a median Tmax of between 2.5 and 2.8 hours post-dose at Day 1 and between 3 and 4 hours post-dose at Week 4. At all doses, plasma concentrations declined in a monophasic manner after reaching Cmax. The start of the elimination phase occurred between 3 and 10 hours post-dose at Day 1 and Week 4, respectively.
These data also showed that after 4 weeks of dosing, 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione accumulated to a small extent (mean accumulation ratios ˜1.02 to 1.52 and ˜0.94 to 1.62 for Cmax and AUC(0-τ), respectively). There was almost a dose proportional increase in AUC(0-τ) and Cmax values with increasing dose. A five-fold higher dose of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione produced a 3.2- and 2.2-fold increase in Cmax at Day 1 and Week 4, respectively. Similarly, a 5-fold increase in dose resulted in a 3.6- and 2.3-fold increase in AUC(0-τ), at Day 1 and Week 4, respectively.
TABLE 1 |
Pharmacokinetic parameters of Actimid ™ in relapsed multiple |
Parameter |
1 mg (N = 6) | 2 mg (N = 2) | 5 mg (N = 3) |
Day 1 |
Cmax | ng/mL | 15.03 | (4.04) | 24.4* | (12.1) | 48.56 | (14.03) |
tmax | h | 3.3 | (2.6) | 2.7* | (0.3) | 2.3 | (0.3) |
AUC(0-∞) | ng · h/mL | 152.90 | (36.62) | 279.18 | (51.10) | 593.10 | (335.23) |
AUC(0-τ) | 134.21 | (27.14) | 249.57 | (29.26) | 520.94 | (267.32) | |
t½ | h | 7.3 | (3.4) | 6.3 | (1.4) | 6.5 | (2.2) |
CL/F | mL/ min | 114.75 | (29.20) | 121.43 | (22.22) | 182.31 | (117.06) |
Vz/f | L | 69.55 | (44.97) | 65.31 | (2.80) | 87.24 | (22.61) |
τ = 24 hours | |||||||
N/A = not available |
TABLE 2 |
Pharmacokinetic parameters of Actimid ™ following multiple oral |
doses(1, 2, and 5 mg/day) in relapsed multiple |
Parameter |
1 mg (N = 5) | 2 mg (N = 2) | 5 mg (N = 3) |
Week 4 |
Cmax | ng/mL | 23.20 | (7.48) | 30.05* | (15.64) | 58.07 | (38.08) |
tmax | h | 3.6 | (1.5) | 2.8* | (0.3) | 5.0 | (2.6) |
AUC(0-∞) | ng · h/mL | N/A | N/A | N/A |
AUC(0-τ) | 239.31 | (122.59) | 269.36 | (186.34) | 597.24 | (354.23) | |
t½ | h | 6.2* | (0.6) | 7.7 | (2.8) | 7.8 | (4.0) |
CL/F | mL/min | 87.85 | (48.48) | 162.68 | (112.54) | 207.50 | (175.41) |
Vz/f | L | 41.35* | (8.84) | 95.04 | (35.39) | 103.95 | (27.25) |
τ = 24 hours | |||||||
N/A = not available | |||||||
*N = 3 patients |
6.5.2 Treatment of Relapsed Multiple Myeloma
Two Phase 1 clinical studies of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Revimid™) have been conducted to identify the maximum tolerated dose (MTD) in patients with refractory or relapsed multiple myeloma. These studies have also characterized the safety profile of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione when ascending doses of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione were given orally for up to 4 weeks. Patients started 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione treatment at 5 mg/day with subsequent escalation to 10, 25, and 50 mg/day. Patients were enrolled for 28 days at their assigned dose, with the option of extended treatment for those who did not exhibit disease progression or experience dose limiting toxicity (DLT). Patients were evaluated for adverse events at each visit and the severity of these events was graded according to the National Cancer Institute (NCI) Common Toxicity Criteria. Patients were discontinued if they experienced DLT (Grade 3 or greater non-hematological, or Grade 4 hematological toxicity).
In this study, 27 patients were enrolled. All patients had relapsed multiple myeloma and 18 (72%) were refractory to salvage therapy. Among these patients, 15 had undergone prior autologous stem cell transplantation and 16 patients had received prior thalidomide treatment. The median number of prior regimens was 3 (range 2 to 6).
Blood and urine samples were collected for analysis of pharmacokinetic parameters on Days 1 and 28. Blood samples were collected according to the following sampling schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose. In addition, a blood sample was collected at each weekly clinic visit for 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione determination. Total urine was collected and pooled according to the following time intervals post-dose: 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours. Response to treatment was assessed by M-protein quantification (by immunoelectrophoresis) from serum and a 24-hour urine collection, with creatinine clearance and 24-hour protein calculations undertaken at screening, baseline, Weeks 2 and 4, and monthly thereafter (or upon early termination). Bone marrow aspirations and/or tissue biopsy are also performed at Months 3, 6 and 12 if a patient's paraprotein serum concentration or 24-hour urine protein excretion declined to the next lower level, based on best response criteria. Preliminary results for the 28-day treatment period are summarized below.
Preliminary pharmacokinetic analyses based on these two studies indicated that AUC and Cmax values increase proportionally with dose following single and multiple doses in multiple myeloma patients (as was seen in healthy volunteers). Further, there was no evidence of accumulation with multiple dosing as single dose AUC(0-∞) was comparable to multiple dose AUC0-τ, following the same dose of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. Similar to healthy volunteer studies, double peaks were observed. Exposure in multiple myeloma patients appeared to be slightly higher based on Cmax and AUC values as compared to healthy male volunteers while clearance in multiple myeloma patients was lower than it was in healthy volunteers, consistent with their poorer renal function (both as a consequence of their age and their disease). Finally, 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione half-live in patients was shorter than in healthy volunteers (mean 8 hours, ranging up to 17 hours).
In this study, the first cohort of 3 patients was treated for 28 days at 5 mg/day without any dose limiting toxicity (DLT). The second cohort of 3 patients subsequently commenced therapy at 10 mg/day. Patients in the second 10 mg/day of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione cohort tolerated treatment well.
6.5.3 Treatment of Solid Tumors
Study with 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Revimid™) was conducted in patients with varying types of solid tumors, including malignant melanoma (13), carcinoma of the pancreas (2), carcinoid-unknown primary (1), renal carcinoma (1), breast carcinoma (1) and NSCLC (2). Patients received 5 mg/day 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for seven days and are subsequently escalated every seven days to 10 mg/day, 25 mg/day, and 50 mg/day for a total of 4 weeks of treatment. Patients who, experienced clinical benefit were permitted to continue on treatment as Named Patients.
The study initially enrolled 20 patients and was subsequently amended to enroll 16 additional patients (adrenal carcinoma, NSCLC, malignant mesothelioma, breast cancer, malignant melanoma (8), renal cell cancer (4)) at a higher dose. The 16 additional patients were given weekly escalating doses of 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, and 150 mg/day over a 6-week period with continuing treatment for an additional six weeks.
The study of Phase 1 study was designed to determine a maximum tolerated dose (MTD) of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in patients with refractory solid tumors and/or lymphoma, as well as to characterize the pharmacokinetic and side effect profiles of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in this patient population. The study design dictates that at least 3 patients must be enrolled at a dose level and have completed 28 days of treatment prior to enrollment of patients at the next higher dose level. Patients in the first cohort began dosing at 5 mg/day of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. Patients will be escalated to 10, 20, 25, and 30 mg/day provided there is no toxicity.
In this study, the MTD is defined as the highest dose level in which fewer than two of six patients treated did not experience Grade 3 or greater non-hematological toxicity or Grade 4 or greater hematological toxicity. If, at any given dose level in either study, one out of three patients experiences toxicity, three additional patients must be treated at that particular dose. If, however, two out of six patients experience DLT, the MTD is judged to have been exceeded. No further dose escalations are to occur and additional patients are to be enrolled at the previous dose level. The dose of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione administered is escalated until the MTD is achieved or the maximum daily dose of is reached.
No DLTs were reported in the initial group of 20 patients enrolled in the study. Thirteen of the original 20 trial patients, along with 2 non-trial patients, continued on treatment as named patients at doses up to 150 mg/day.
6.5.4 Treatment of Gliomas
This study was performed to find toxicity in patients with recurrent, high-grade gliomas. The study is designed such that patients are given increasingly higher doses of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione until a maximum tolerated dose (MTD) is established. The study also seeks to obtain preliminary toxicity information and pharmacokinetic data on 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, as well as to develop exploratory data concerning surrogate end points of angiogenic activity in vivo using functional neuro-imaging studies, and in vitro assays of serum angiogenic peptides.
Patients enrolled in the first cohort receive 2.5 mg/m2/day for a 4-week cycle. During each 4-week cycle of therapy, 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione administered once daily for 3 weeks followed by a week of rest. Patients who complete a treatment cycle may receive another cycle of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione treatment if two criteria are met. First, the patient must have stable disease or have experienced a partial response or complete response, or the patient is benefiting from the therapy with 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as evidenced by a decrease in tumor-related symptoms such as neurological deficits. Second, the patient must have recovered from toxicity related to 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione which occurred in the prior cycle by Day 42 or sooner (28-day cycle plus limit of 2 weeks to recover) as evidenced by a return to Grade≦1 toxicity level. Patients who experience DLT in the previous cycle should have their dose modified. DLT is defined as an non-hematological event Grade≧3 toxicity or hematological event of Grade 4 toxicity thought to be related to the study medication. Patients who experience DLT in the first cycle and have no response to therapy are removed from the study.
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione doses are subsequently escalated to 5, 8, 11, 15, and 20 mg/m2/day to a maximum total daily dose of 40 mg. Patients continue to receive 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione on a 4-week cycle per dose level until one of the off-study criteria are met.
Three patients are enrolled in each cohort. If at least one DLT occurs, three additional patients are added to the cohort at that particular dose level. If two DLTs occur, the MTD, defined as the dose at which fewer than one-third of patients at each dose level experiences DLT has been exceeded and four more patients are treated at the previous dose.
Patients who experience DLT during the first 4-week cycle are removed from the study, except if they have a response to therapy. For patients who have completed their first 4-week cycle of without DLT, but who subsequently experience Grade 3 or 4 hematological and/or nonhematological toxicity, treatment is suspended for a minimum of a week. If the toxicity resolves to <Grade 2 within three weeks, the patient is treated at two dose levels lower than the dose that caused the toxicity (or a 50% reduction if the patient was treated at the first or second dose level). Patients in whom Grade 3 or 4 toxicity does not resolve to <Grade 1 within three weeks, or those who have another Grade 3 toxicity at the reduced dose are removed from the study.
Pharmacokinetic sampling is performed prior the first dose of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Day 1) and 0.5, 1, 2, 4, 6, 8, 24, and 48 hours thereafter. Sampling is also conducted pre-dose on Days 7 and 21 and 0.5, 1, 2, 4, 6, 8, and 24 post-dose on Day 21 to evaluate steady-state 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione levels.
6.5.5 Treatment of Metastatic Melanoma
Patients with metastatic melanoma were started on 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Revmid™) at 5 mg/day for seven days. The dose was then increased every seven days to 10 mg/day, 25 mg/day, and 50 mg/day, respectively, for a total of four weeks on therapy. Five of the 13 melanoma patients who were treated under this regimen either showed disease stabilization or a partial response in the first four weeks of treatment. Tumor response was seen in cutaneous and subcutaneous lesions (five patients), lymph nodes (two patients), and liver (one patient). The duration of response was approximately six months. The result suggests that the compound appears is a promising new anti-cancer agent and has both antiangiogenic and immunomodulatory properties.
6.5.6 Treatment of Relapsed or Refractory Multiple Myeloma
Patients with relapsed and refractory Dune-Salmon stage III multiple myeloma, who have either failed at least three previous regimens or presented with poor performance status, neutropenia or thrombocytopenia, are treated with up to four cycles of combination of melphalan (50 mg intravenously), an immunomodulatory compound of the invention (about 1 to 150 mg orally daily), and dexamethasone (40 mg/day orally on days 1 to 4) every four to six weeks. Maintenance treatment consisting of daily an immunomodulatory compound of the invention and monthly dexamethasone are continued until the disease progression. The therapy using an immunomodulatory compound of the invention in combination with melphalan and dexamethasone is highly active and generally tolerated in heavily pretreated multiple myeloma patients whose prognosis is otherwise poor.
The embodiments of the invention described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.
Claims (28)
1. A method of treating hepatocellular carcinoma, which comprises administering to a patient having hepatocellular carcinoma about 5 to about 25 mg per day of a compound 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione of the formula:
2. The method of claim 1 , wherein the hepatocellular carcinoma is metastatic hepatocellular carcinoma, unrescectable hepatocellular carcinoma, refractory hepatocellular carcinoma, or relapsed hepatocellular carcinoma.
4. The method of claim 1 , wherein the compound is a pharmaceutically acceptable salt.
5. The method of claim 1 , wherein the compound is a pharmaceutically acceptable solvate.
6. The method of claim 1 , wherein the compound is a pharmaceutically acceptable stereoisomer.
7. The method of claim 6 , wherein the stereoisomer is an enantiomerically pure R isomer.
8. The method of claim 6 , wherein the stereoisomer is an enantiomerically pure S isomer.
9. The method of claim 1 , which further comprises administering a therapeutically effective amount of a second active agent.
10. The method of claim 9 , wherein the second active agent is hematopoietic growth factor, a cytokine, or an anti-cancer agent.
11. The method of claim 9 , wherein the second active agent is interferon alpha, capecitabine, cisplatin. thiotepa, foxorubicin, sorafenib, cetuximab, gemcitabine, bevacizumab, oxaliplatin, temserolimus, everolimus, ifosfamide, carboplatin, etoposide, 5-fluorouracil, vincristine, cyclophosphamide, epirubicin, paclitaxel. octreotide, geftinib, erlotinib, sunitinib, cediranib, bortezomib, azacitidine, amrubicin, anthracycline, or a combination thereof.
12. The method of claim 1 , wherein the hepatocellular carcinoma is relapsed. refractory or resistant to conventional therapy.
13. The method of claim 1 , wherein the compound is administered orally.
14. The method of claim 13 , wherein the compound is administered in the form of a capsule or tablet.
15. The method of claim 1 , wherein the compound is administered in an amount of from about 10 to about 25 mg per day.
16. The method of claim 14 , wherein the compound is administered in an amount of about 2.5, 5, 10, 15, 20, or 25 per day.
17. The method of claim 1 , wherein the compound is administered in an amount of about 25 mg per day.
18. The method of claim 1 , wherein the compound is administered cyclically.
19. The method of claim 18 , wherein one cycle comprises four to six weeks.
20. The method of claim 18 , wherein one cycle comprises the administration of the compound for 21 days followed by seven days rest.
21. The method of claim 18 , wherein the compound is administered for four to twenty-four weeks with one to six weeks of rest.
22. The method of claim 1 , wherein the compound is administered in an amount of from about 5 to about 25 mg per day for days 1-21 every 28 days.
23. The method of claim 18 , wherein the compound is administered in an amount of about 25 mg per day for 21 days followed by seven days rest in a 28 day cycle.
24. The method of claim 1 , wherein the compound is administered in an amount of about 5 mg per day.
25. The method of claim 1 , wherein the compound is administered in an amount of 10 mg per day.
26. The method of claim 1 , wherein the compound is administered in an amount of 15 mg per day.
27. The method of claim 1 , wherein the compound is administered in a capsule comprising 5 mg, 10 mg, 15 mg or 25 mg of the compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof.
28. The method of claim 14 , wherein the capsule comprises the compound, lactose anhydrous, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.
Priority Applications (1)
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US12/755,904 US8410136B2 (en) | 2002-05-17 | 2010-04-07 | Methods for treatment of hepatocellular carcinoma using 3-(4-amino-1-OXO-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione |
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US38084202P | 2002-05-17 | 2002-05-17 | |
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US10/438,213 US7968569B2 (en) | 2002-05-17 | 2003-05-15 | Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US12/755,904 US8410136B2 (en) | 2002-05-17 | 2010-04-07 | Methods for treatment of hepatocellular carcinoma using 3-(4-amino-1-OXO-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione |
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US10/438,213 Expired - Lifetime US7968569B2 (en) | 2002-05-17 | 2003-05-15 | Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US11/102,742 Expired - Lifetime US7468363B2 (en) | 2002-05-17 | 2005-04-08 | Methods for treatment of cancers using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US11/267,896 Abandoned US20060069065A1 (en) | 2002-05-17 | 2005-11-04 | Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases |
US11/325,954 Abandoned US20060105993A1 (en) | 2002-05-17 | 2006-01-04 | Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases |
US11/370,560 Abandoned US20060172970A1 (en) | 2002-05-17 | 2006-03-07 | Methods for treatment and management of lung cancer using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione |
US11/881,756 Abandoned US20070299020A1 (en) | 2002-05-17 | 2007-07-27 | Methods for treatment of ovarian, colorectal or pancreatic cancer using 4-(aminno)-2(2,6-dioxo(3-piperidyl)-isoindoline-1,3-dione |
US12/148,796 Abandoned US20090010877A1 (en) | 2002-05-17 | 2008-04-22 | Methods for treatment prostate cancer using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US12/150,341 Abandoned US20080206193A1 (en) | 2002-05-17 | 2008-04-25 | Method for treatment and management of thyroid cancer using immunomodulatory compounds |
US12/151,757 Abandoned US20080219948A1 (en) | 2002-05-17 | 2008-05-08 | Methods for treatment of behcet's disease using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US12/151,759 Abandoned US20080286232A1 (en) | 2002-05-17 | 2008-05-08 | Methods for treating sarcoma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione or 4-(amino)-2-(2,6 dioxo(3-piperidyl))-isoindoline-1,3-dione |
US12/151,758 Expired - Lifetime US8207200B2 (en) | 2002-05-17 | 2008-05-08 | Methods for treating multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydroindol-2-yl)-piperidine-2,6-dione follow by autologous stem cell transplantation |
US12/151,760 Abandoned US20080219949A1 (en) | 2002-05-17 | 2008-05-08 | Methods for treating brain cancer using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione or 4-(amino)-2-(2,6 dioxo(3-piperidyl))-isoindoline-1,3-dione |
US12/229,074 Active 2025-04-23 US8198262B2 (en) | 2002-05-17 | 2008-08-19 | Methods for treating multiple myeloma using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione |
US12/229,075 Abandoned US20080317709A1 (en) | 2002-05-17 | 2008-08-19 | Methods for treating head or neck cancer using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione |
US12/354,249 Abandoned US20090123416A1 (en) | 2002-05-17 | 2009-01-15 | Methods for the treatment of bladder cancer using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione |
US12/388,886 Expired - Fee Related US8188118B2 (en) | 2002-05-17 | 2009-02-19 | Method for treating multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with antibodies |
US12/621,038 Abandoned US20100063094A1 (en) | 2002-05-17 | 2009-11-18 | Methods for treatment of colorectal cancer using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US12/640,702 Expired - Fee Related US8198306B2 (en) | 2002-05-17 | 2009-12-17 | Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with a proteasome inhibitor |
US12/641,245 Abandoned US20100099711A1 (en) | 2002-05-17 | 2009-12-17 | Methods and Compositions Using Immunomodulatory Compounds for The Treatment and Management of Cancers and Other Diseases |
US12/755,875 Active 2024-12-11 US8492406B2 (en) | 2002-05-17 | 2010-04-07 | Methods for treatment of follicular lymphoma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione |
US12/755,904 Expired - Lifetime US8410136B2 (en) | 2002-05-17 | 2010-04-07 | Methods for treatment of hepatocellular carcinoma using 3-(4-amino-1-OXO-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione |
US13/276,867 Abandoned US20120035145A1 (en) | 2002-05-17 | 2011-10-19 | Methods of treating multiple myeloma using melphalan, prednisone and lenalidomide |
US13/483,832 Expired - Lifetime US8722647B2 (en) | 2002-05-17 | 2012-05-30 | Methods for treating amyloidosis using 4-(amino)-2-(2,6-Dioxo(3-piperidyl))- isoindoline-1,3-dione |
US13/488,888 Expired - Lifetime US8648095B2 (en) | 2002-05-17 | 2012-06-05 | Methods for treating multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with proteasome inhibitor |
US13/740,969 Expired - Lifetime US8759375B2 (en) | 2002-05-17 | 2013-01-14 | Methods for treating multiple myeloma using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione in combination with proteasome inhibitor |
US13/782,612 Expired - Lifetime US8735428B2 (en) | 2002-05-17 | 2013-03-01 | Methods for treating multiple myeloma with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione |
US13/782,728 Expired - Lifetime US8673939B2 (en) | 2002-05-17 | 2013-03-01 | Methods for treating multiple myeloma with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione |
US13/858,708 Expired - Lifetime US8530498B1 (en) | 2002-05-17 | 2013-04-08 | Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione |
US13/942,232 Expired - Lifetime US8722705B2 (en) | 2002-05-17 | 2013-07-15 | Methods for treating diffuse large B-cell lymphoma with 3-(4-amino-1-OXO-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with second active agents |
US14/201,069 Expired - Fee Related US9283215B2 (en) | 2002-05-17 | 2014-03-07 | Methods for treating multiple myeloma using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione in combination with antibodies |
US14/224,974 Expired - Lifetime US9050324B2 (en) | 2002-05-17 | 2014-03-25 | Methods for treating amyloidosis with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione |
US14/225,970 Expired - Lifetime US9155730B2 (en) | 2002-05-17 | 2014-03-26 | Methods for treating non-hodgkin's lymphoma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with a second active agent |
US14/255,211 Expired - Lifetime US9101621B2 (en) | 2002-05-17 | 2014-04-17 | Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation |
US14/482,745 Expired - Lifetime US9101622B2 (en) | 2002-05-17 | 2014-09-10 | Methods for treating newly diagnosed multiple myeloma 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in combination with dexamethasone |
US14/563,613 Expired - Lifetime US9393238B2 (en) | 2002-05-17 | 2014-12-08 | Methods for treating non-hodgkin's lymphoma with 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in combination with a second active agent |
US14/564,693 Abandoned US20150094336A1 (en) | 2002-05-17 | 2014-12-09 | Methods for treating gliomas with 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US14/662,788 Abandoned US20150190386A1 (en) | 2002-05-17 | 2015-03-19 | Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl) piperidine-2,6-dione in combination with second active agents |
US14/864,121 Abandoned US20160008345A1 (en) | 2002-05-17 | 2015-09-24 | Methods for treating gliomas with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione |
US15/161,048 Expired - Lifetime US9662321B2 (en) | 2002-05-17 | 2016-05-20 | Methods for treating newly diagnosed multiple myeloma with 3-(4-amino-1-OXO-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with second active agents |
US15/397,643 Ceased US10206914B2 (en) | 2002-05-17 | 2017-01-03 | Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation |
US16/277,936 Abandoned US20190175575A1 (en) | 2002-05-17 | 2019-02-15 | Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases |
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US10/438,213 Expired - Lifetime US7968569B2 (en) | 2002-05-17 | 2003-05-15 | Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US11/102,742 Expired - Lifetime US7468363B2 (en) | 2002-05-17 | 2005-04-08 | Methods for treatment of cancers using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US11/267,896 Abandoned US20060069065A1 (en) | 2002-05-17 | 2005-11-04 | Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases |
US11/325,954 Abandoned US20060105993A1 (en) | 2002-05-17 | 2006-01-04 | Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases |
US11/370,560 Abandoned US20060172970A1 (en) | 2002-05-17 | 2006-03-07 | Methods for treatment and management of lung cancer using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione |
US11/881,756 Abandoned US20070299020A1 (en) | 2002-05-17 | 2007-07-27 | Methods for treatment of ovarian, colorectal or pancreatic cancer using 4-(aminno)-2(2,6-dioxo(3-piperidyl)-isoindoline-1,3-dione |
US12/148,796 Abandoned US20090010877A1 (en) | 2002-05-17 | 2008-04-22 | Methods for treatment prostate cancer using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US12/150,341 Abandoned US20080206193A1 (en) | 2002-05-17 | 2008-04-25 | Method for treatment and management of thyroid cancer using immunomodulatory compounds |
US12/151,757 Abandoned US20080219948A1 (en) | 2002-05-17 | 2008-05-08 | Methods for treatment of behcet's disease using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US12/151,759 Abandoned US20080286232A1 (en) | 2002-05-17 | 2008-05-08 | Methods for treating sarcoma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione or 4-(amino)-2-(2,6 dioxo(3-piperidyl))-isoindoline-1,3-dione |
US12/151,758 Expired - Lifetime US8207200B2 (en) | 2002-05-17 | 2008-05-08 | Methods for treating multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydroindol-2-yl)-piperidine-2,6-dione follow by autologous stem cell transplantation |
US12/151,760 Abandoned US20080219949A1 (en) | 2002-05-17 | 2008-05-08 | Methods for treating brain cancer using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione or 4-(amino)-2-(2,6 dioxo(3-piperidyl))-isoindoline-1,3-dione |
US12/229,074 Active 2025-04-23 US8198262B2 (en) | 2002-05-17 | 2008-08-19 | Methods for treating multiple myeloma using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione |
US12/229,075 Abandoned US20080317709A1 (en) | 2002-05-17 | 2008-08-19 | Methods for treating head or neck cancer using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione |
US12/354,249 Abandoned US20090123416A1 (en) | 2002-05-17 | 2009-01-15 | Methods for the treatment of bladder cancer using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione |
US12/388,886 Expired - Fee Related US8188118B2 (en) | 2002-05-17 | 2009-02-19 | Method for treating multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with antibodies |
US12/621,038 Abandoned US20100063094A1 (en) | 2002-05-17 | 2009-11-18 | Methods for treatment of colorectal cancer using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US12/640,702 Expired - Fee Related US8198306B2 (en) | 2002-05-17 | 2009-12-17 | Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with a proteasome inhibitor |
US12/641,245 Abandoned US20100099711A1 (en) | 2002-05-17 | 2009-12-17 | Methods and Compositions Using Immunomodulatory Compounds for The Treatment and Management of Cancers and Other Diseases |
US12/755,875 Active 2024-12-11 US8492406B2 (en) | 2002-05-17 | 2010-04-07 | Methods for treatment of follicular lymphoma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione |
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US13/276,867 Abandoned US20120035145A1 (en) | 2002-05-17 | 2011-10-19 | Methods of treating multiple myeloma using melphalan, prednisone and lenalidomide |
US13/483,832 Expired - Lifetime US8722647B2 (en) | 2002-05-17 | 2012-05-30 | Methods for treating amyloidosis using 4-(amino)-2-(2,6-Dioxo(3-piperidyl))- isoindoline-1,3-dione |
US13/488,888 Expired - Lifetime US8648095B2 (en) | 2002-05-17 | 2012-06-05 | Methods for treating multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with proteasome inhibitor |
US13/740,969 Expired - Lifetime US8759375B2 (en) | 2002-05-17 | 2013-01-14 | Methods for treating multiple myeloma using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione in combination with proteasome inhibitor |
US13/782,612 Expired - Lifetime US8735428B2 (en) | 2002-05-17 | 2013-03-01 | Methods for treating multiple myeloma with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione |
US13/782,728 Expired - Lifetime US8673939B2 (en) | 2002-05-17 | 2013-03-01 | Methods for treating multiple myeloma with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione |
US13/858,708 Expired - Lifetime US8530498B1 (en) | 2002-05-17 | 2013-04-08 | Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione |
US13/942,232 Expired - Lifetime US8722705B2 (en) | 2002-05-17 | 2013-07-15 | Methods for treating diffuse large B-cell lymphoma with 3-(4-amino-1-OXO-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with second active agents |
US14/201,069 Expired - Fee Related US9283215B2 (en) | 2002-05-17 | 2014-03-07 | Methods for treating multiple myeloma using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione in combination with antibodies |
US14/224,974 Expired - Lifetime US9050324B2 (en) | 2002-05-17 | 2014-03-25 | Methods for treating amyloidosis with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione |
US14/225,970 Expired - Lifetime US9155730B2 (en) | 2002-05-17 | 2014-03-26 | Methods for treating non-hodgkin's lymphoma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with a second active agent |
US14/255,211 Expired - Lifetime US9101621B2 (en) | 2002-05-17 | 2014-04-17 | Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation |
US14/482,745 Expired - Lifetime US9101622B2 (en) | 2002-05-17 | 2014-09-10 | Methods for treating newly diagnosed multiple myeloma 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in combination with dexamethasone |
US14/563,613 Expired - Lifetime US9393238B2 (en) | 2002-05-17 | 2014-12-08 | Methods for treating non-hodgkin's lymphoma with 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in combination with a second active agent |
US14/564,693 Abandoned US20150094336A1 (en) | 2002-05-17 | 2014-12-09 | Methods for treating gliomas with 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US14/662,788 Abandoned US20150190386A1 (en) | 2002-05-17 | 2015-03-19 | Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl) piperidine-2,6-dione in combination with second active agents |
US14/864,121 Abandoned US20160008345A1 (en) | 2002-05-17 | 2015-09-24 | Methods for treating gliomas with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione |
US15/161,048 Expired - Lifetime US9662321B2 (en) | 2002-05-17 | 2016-05-20 | Methods for treating newly diagnosed multiple myeloma with 3-(4-amino-1-OXO-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with second active agents |
US15/397,643 Ceased US10206914B2 (en) | 2002-05-17 | 2017-01-03 | Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation |
US16/277,936 Abandoned US20190175575A1 (en) | 2002-05-17 | 2019-02-15 | Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases |
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US20040091455A1 (en) * | 2002-10-31 | 2004-05-13 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for treatment and management of macular degeneration |
US7563810B2 (en) * | 2002-11-06 | 2009-07-21 | Celgene Corporation | Methods of using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myeloproliferative diseases |
US8034831B2 (en) * | 2002-11-06 | 2011-10-11 | Celgene Corporation | Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-Dioxo(3-piperidyl)-isoindoline-1,3-dione in combination with other therapies |
BR0316256A (en) * | 2002-11-18 | 2005-10-04 | Celgene Corp | Methods of inhibiting tnf-alpha production and pde4 activity, treating or preventing a disease or disorder, controlling camp levels in a cell and producing a compound, pharmaceutical composition and compound |
JP2006510617A (en) * | 2002-11-18 | 2006-03-30 | セルジーン・コーポレーション | Method of using (+)-3- (3,4-dimethoxy-phenyl) -3- (1-oxo-1,3-dihydro-isoindol-2-yl) -propionamide and compositions containing it |
CL2004001004A1 (en) * | 2003-05-19 | 2005-03-18 | Upjohn Co | PHARMACEUTICAL COMBINATION THAT INCLUDES IRINOTECAN AND REVIMID TO TREAT MULTIPLE MYELOMA. |
US20070084897A1 (en) | 2003-05-20 | 2007-04-19 | Shelton Frederick E Iv | Articulating surgical stapling instrument incorporating a two-piece e-beam firing mechanism |
US9060770B2 (en) | 2003-05-20 | 2015-06-23 | Ethicon Endo-Surgery, Inc. | Robotically-driven surgical instrument with E-beam driver |
UA83504C2 (en) * | 2003-09-04 | 2008-07-25 | Селджин Корпорейшн | Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US20080027113A1 (en) * | 2003-09-23 | 2008-01-31 | Zeldis Jerome B | Methods of Using and Compositions Comprising Immunomodulatory Compounds for Treatment and Management of Macular Degeneration |
US7612096B2 (en) * | 2003-10-23 | 2009-11-03 | Celgene Corporation | Methods for treatment, modification and management of radiculopathy using 1-oxo-2-(2,6-dioxopiperidin-3yl)-4-aminoisoindoline |
EA200600921A1 (en) * | 2003-11-06 | 2006-10-27 | Селджин Корпорейшн | METHODS AND COMPOSITIONS WITH THE USE OF TALIDOMIDE FOR THE TREATMENT AND MANAGEMENT OF CANCER AND OTHER DISEASES |
US20050100529A1 (en) * | 2003-11-06 | 2005-05-12 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of asbestos-related diseases and disorders |
NZ548049A (en) * | 2003-12-02 | 2009-01-31 | Celgene Corp | Methods and compositions for the treatment and management of hemoglobinopathy and anemia |
US20050143344A1 (en) * | 2003-12-30 | 2005-06-30 | Zeldis Jerome B. | Methods and compositions using immunomodulatory compounds for the treatment and management of central nervous system disorders or diseases |
NZ550026A (en) * | 2004-03-22 | 2009-10-30 | Celgene Corp | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of skin diseases or disorders |
GB0406445D0 (en) * | 2004-03-23 | 2004-04-28 | Astrazeneca Ab | Combination therapy |
US20100009929A1 (en) | 2004-03-29 | 2010-01-14 | Cheng Jin Q | Compositions including triciribine and bortezomib and derivatives thereof and methods of use thereof |
US20100028339A1 (en) | 2004-03-29 | 2010-02-04 | Cheng Jin Q | Compositions including triciribine and trastuzumab and methods of use thereof |
LT2574341T (en) | 2004-03-29 | 2017-09-11 | University Of South Florida | Effective treatment of tumors and cancer with triciribine phosphate |
US20100173864A1 (en) * | 2004-03-29 | 2010-07-08 | Cheng Jin Q | Compositions including triciribine and one or more platinum compounds and methods of use thereof |
US20100009928A1 (en) | 2004-03-29 | 2010-01-14 | Cheng Jin Q | Compositions including triciribine and taxanes and methods of use thereof |
US20110008327A1 (en) | 2004-03-29 | 2011-01-13 | Cheng Jin Q | Compositions including triciribine and epidermal growth factor receptor inhibitor compounds or salts thereof and methods of use thereof |
US20050222209A1 (en) * | 2004-04-01 | 2005-10-06 | Zeldis Jerome B | Methods and compositions for the treatment, prevention or management of dysfunctional sleep and dysfunctional sleep associated with disease |
JP2007532642A (en) * | 2004-04-14 | 2007-11-15 | セルジーン・コーポレーション | Use of selective cytokine inhibitors for the treatment and management of myelodysplastic syndromes and compositions containing the same |
BRPI0418742A (en) * | 2004-04-14 | 2007-09-11 | Celgene Corp | methods of treating, preventing or controlling a myelodysplastic syndrome, reducing or preventing an adverse effect associated with the administration of a second active ingredient in a patient suffering from a myelodysplastic syndrome, pharmaceutical composition, single unit dosage form, and kit |
CA2563810A1 (en) * | 2004-04-23 | 2005-11-10 | Celgene Corporation | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of pulmonary hypertension |
CN1984651A (en) * | 2004-05-05 | 2007-06-20 | 细胞基因公司 | Methods and compositions using selective cytokine inhibitory drugs for treatment and management of cancers and other diseases |
US9072535B2 (en) | 2011-05-27 | 2015-07-07 | Ethicon Endo-Surgery, Inc. | Surgical stapling instruments with rotatable staple deployment arrangements |
US8215531B2 (en) | 2004-07-28 | 2012-07-10 | Ethicon Endo-Surgery, Inc. | Surgical stapling instrument having a medical substance dispenser |
US11896225B2 (en) | 2004-07-28 | 2024-02-13 | Cilag Gmbh International | Staple cartridge comprising a pan |
US11998198B2 (en) | 2004-07-28 | 2024-06-04 | Cilag Gmbh International | Surgical stapling instrument incorporating a two-piece E-beam firing mechanism |
ZA200702382B (en) * | 2004-09-03 | 2008-08-27 | Celgene Corp | Processes for the preparation of substituted 2-(2,6-dioxoplperidin-3-yl)-1-oxoisoindolines |
US20060122228A1 (en) * | 2004-11-23 | 2006-06-08 | Zeldis Jerome B | Methods and compositions using immunomodulatory compounds for treatment and management of central nervous system injury |
AU2005315912A1 (en) * | 2004-12-13 | 2006-06-22 | F. Hoffmann-La Roche Ag | Novel pharmaceutical composition containing at least one Dolastatin 10 derivative |
US20110116468A1 (en) * | 2005-01-04 | 2011-05-19 | Yuan Zhu | Handover of user equipment |
US7595380B2 (en) | 2005-04-27 | 2009-09-29 | Tripath Imaging, Inc. | Monoclonal antibodies and methods for their use in the detection of cervical disease |
US20060270707A1 (en) * | 2005-05-24 | 2006-11-30 | Zeldis Jerome B | Methods and compositions using 4-[(cyclopropanecarbonylamino)methyl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione for the treatment or prevention of cutaneous lupus |
US20060287257A1 (en) * | 2005-06-20 | 2006-12-21 | Stockel Richard F | Pharmaceutical compositions to treat diseases caused by mycobacterium |
CA2612612C (en) | 2005-06-30 | 2014-03-11 | Celgene Corporation | Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds |
CA2616230A1 (en) * | 2005-07-22 | 2007-02-01 | Trf Pharma, Inc. | Method for treating sickle cell disease and sickle cell disease sequelae |
US7507842B2 (en) | 2005-08-12 | 2009-03-24 | Radiorx, Inc. | Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereof |
US11484312B2 (en) | 2005-08-31 | 2022-11-01 | Cilag Gmbh International | Staple cartridge comprising a staple driver arrangement |
US7669746B2 (en) | 2005-08-31 | 2010-03-02 | Ethicon Endo-Surgery, Inc. | Staple cartridges for forming staples having differing formed staple heights |
US11246590B2 (en) | 2005-08-31 | 2022-02-15 | Cilag Gmbh International | Staple cartridge including staple drivers having different unfired heights |
US10159482B2 (en) | 2005-08-31 | 2018-12-25 | Ethicon Llc | Fastener cartridge assembly comprising a fixed anvil and different staple heights |
US9237891B2 (en) | 2005-08-31 | 2016-01-19 | Ethicon Endo-Surgery, Inc. | Robotically-controlled surgical stapling devices that produce formed staples having different lengths |
US7934630B2 (en) | 2005-08-31 | 2011-05-03 | Ethicon Endo-Surgery, Inc. | Staple cartridges for forming staples having differing formed staple heights |
US20080138295A1 (en) * | 2005-09-12 | 2008-06-12 | Celgene Coporation | Bechet's disease using cyclopropyl-N-carboxamide |
US20070212397A1 (en) * | 2005-09-15 | 2007-09-13 | Roth Daniel B | Pharmaceutical delivery device and method for providing ocular treatment |
US20070071754A1 (en) * | 2005-09-26 | 2007-03-29 | Peyman Gholam A | Method to ameliorate inflammation |
US20070106317A1 (en) | 2005-11-09 | 2007-05-10 | Shelton Frederick E Iv | Hydraulically and electrically actuated articulation joints for surgical instruments |
NZ595196A (en) | 2005-11-09 | 2013-03-28 | Proteolix Inc | Peptide-based compounds for enzyme inhibition |
CN1870631B (en) * | 2005-11-11 | 2010-04-14 | 华为技术有限公司 | Gate control method of media gateway |
US7632498B2 (en) | 2005-12-19 | 2009-12-15 | Tripath Imaging, Inc. | MCM6 and MCM7 monoclonal antibodies and methods for their use in the detection of cervical disease |
KR20080097190A (en) * | 2005-12-29 | 2008-11-04 | 안트로제네시스 코포레이션 | Improved composition for collecting and preserving placental stem cells and methods of using the composition |
US20070155791A1 (en) * | 2005-12-29 | 2007-07-05 | Zeldis Jerome B | Methods for treating cutaneous lupus using aminoisoindoline compounds |
US7753904B2 (en) | 2006-01-31 | 2010-07-13 | Ethicon Endo-Surgery, Inc. | Endoscopic surgical instrument with a handle that can articulate with respect to the shaft |
US8708213B2 (en) | 2006-01-31 | 2014-04-29 | Ethicon Endo-Surgery, Inc. | Surgical instrument having a feedback system |
US11224427B2 (en) | 2006-01-31 | 2022-01-18 | Cilag Gmbh International | Surgical stapling system including a console and retraction assembly |
US8820603B2 (en) | 2006-01-31 | 2014-09-02 | Ethicon Endo-Surgery, Inc. | Accessing data stored in a memory of a surgical instrument |
US8186555B2 (en) | 2006-01-31 | 2012-05-29 | Ethicon Endo-Surgery, Inc. | Motor-driven surgical cutting and fastening instrument with mechanical closure system |
US11278279B2 (en) | 2006-01-31 | 2022-03-22 | Cilag Gmbh International | Surgical instrument assembly |
US20120292367A1 (en) | 2006-01-31 | 2012-11-22 | Ethicon Endo-Surgery, Inc. | Robotically-controlled end effector |
US20110024477A1 (en) | 2009-02-06 | 2011-02-03 | Hall Steven G | Driven Surgical Stapler Improvements |
US7845537B2 (en) | 2006-01-31 | 2010-12-07 | Ethicon Endo-Surgery, Inc. | Surgical instrument having recording capabilities |
US11793518B2 (en) | 2006-01-31 | 2023-10-24 | Cilag Gmbh International | Powered surgical instruments with firing system lockout arrangements |
US20110290856A1 (en) | 2006-01-31 | 2011-12-01 | Ethicon Endo-Surgery, Inc. | Robotically-controlled surgical instrument with force-feedback capabilities |
US8992422B2 (en) | 2006-03-23 | 2015-03-31 | Ethicon Endo-Surgery, Inc. | Robotically-controlled endoscopic accessory channel |
US20080064876A1 (en) * | 2006-05-16 | 2008-03-13 | Muller George W | Process for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione |
PL2041158T3 (en) | 2006-06-19 | 2013-08-30 | Onyx Therapeutics Inc | Peptide epoxyketones for proteasome inhibition |
US8322455B2 (en) | 2006-06-27 | 2012-12-04 | Ethicon Endo-Surgery, Inc. | Manually driven surgical cutting and fastening instrument |
CL2007002218A1 (en) * | 2006-08-03 | 2008-03-14 | Celgene Corp Soc Organizada Ba | USE OF 3- (4-AMINO-1-OXO-1,3-DIHIDRO-ISOINDOL-2-IL) -PIPERIDINE 2,6-DIONA FOR THE PREPARATION OF A USEFUL MEDICINAL PRODUCT FOR THE TREATMENT OF LAYER CELL LYMPHOMA. |
AU2007281684C1 (en) * | 2006-08-07 | 2013-12-19 | Abbvie Biotherapeutics Inc. | Methods of treating multiple myeloma using combination therapies based on anti-CS1 antibodies |
US8877780B2 (en) | 2006-08-30 | 2014-11-04 | Celgene Corporation | 5-substituted isoindoline compounds |
DK2076260T3 (en) * | 2006-09-15 | 2011-06-27 | Celgene Corp | N-methylaminomethyl-isoindole compounds and compositions containing them, and methods for their use |
PL2420498T3 (en) | 2006-09-26 | 2017-10-31 | Celgene Corp | 5-substituted quinazolinone derivatives as anti-cancer agents |
US10568652B2 (en) | 2006-09-29 | 2020-02-25 | Ethicon Llc | Surgical staples having attached drivers of different heights and stapling instruments for deploying the same |
US11980366B2 (en) | 2006-10-03 | 2024-05-14 | Cilag Gmbh International | Surgical instrument |
JP2010506937A (en) * | 2006-10-19 | 2010-03-04 | セルジーン・コーポレーション | Methods and compositions using immunomodulatory compounds for the treatment and management of spirochetes and other obligate intracellular bacterial diseases |
US8684253B2 (en) | 2007-01-10 | 2014-04-01 | Ethicon Endo-Surgery, Inc. | Surgical instrument with wireless communication between a control unit of a robotic system and remote sensor |
US8632535B2 (en) | 2007-01-10 | 2014-01-21 | Ethicon Endo-Surgery, Inc. | Interlock and surgical instrument including same |
US11291441B2 (en) | 2007-01-10 | 2022-04-05 | Cilag Gmbh International | Surgical instrument with wireless communication between control unit and remote sensor |
US7434717B2 (en) | 2007-01-11 | 2008-10-14 | Ethicon Endo-Surgery, Inc. | Apparatus for closing a curved anvil of a surgical stapling device |
US11039836B2 (en) | 2007-01-11 | 2021-06-22 | Cilag Gmbh International | Staple cartridge for use with a surgical stapling instrument |
US7604151B2 (en) | 2007-03-15 | 2009-10-20 | Ethicon Endo-Surgery, Inc. | Surgical stapling systems and staple cartridges for deploying surgical staples with tissue compression features |
US8931682B2 (en) | 2007-06-04 | 2015-01-13 | Ethicon Endo-Surgery, Inc. | Robotically-controlled shaft based rotary drive systems for surgical instruments |
US11857181B2 (en) | 2007-06-04 | 2024-01-02 | Cilag Gmbh International | Robotically-controlled shaft based rotary drive systems for surgical instruments |
US7753245B2 (en) | 2007-06-22 | 2010-07-13 | Ethicon Endo-Surgery, Inc. | Surgical stapling instruments |
US11849941B2 (en) | 2007-06-29 | 2023-12-26 | Cilag Gmbh International | Staple cartridge having staple cavities extending at a transverse angle relative to a longitudinal cartridge axis |
US7893045B2 (en) | 2007-08-07 | 2011-02-22 | Celgene Corporation | Methods for treating lymphomas in certain patient populations and screening patients for said therapy |
CN101952272B (en) | 2007-09-26 | 2014-08-27 | 细胞基因公司 | 6-, 7-, or 8-substituted quinazolinone derivatives and compositions comprising and methods of using the same |
PL2207791T5 (en) | 2007-10-04 | 2020-07-27 | Onyx Therapeutics, Inc. | Crystalline peptide epoxy ketone protease inhibitors and the synthesis of amino acid keto-epoxides |
US20100311683A1 (en) * | 2007-11-01 | 2010-12-09 | Beach C L | Cytidine analogs for treatment of myelodysplastic syndromes |
US7866527B2 (en) | 2008-02-14 | 2011-01-11 | Ethicon Endo-Surgery, Inc. | Surgical stapling apparatus with interlockable firing system |
US7819298B2 (en) | 2008-02-14 | 2010-10-26 | Ethicon Endo-Surgery, Inc. | Surgical stapling apparatus with control features operable with one hand |
US9179912B2 (en) | 2008-02-14 | 2015-11-10 | Ethicon Endo-Surgery, Inc. | Robotically-controlled motorized surgical cutting and fastening instrument |
US11986183B2 (en) | 2008-02-14 | 2024-05-21 | Cilag Gmbh International | Surgical cutting and fastening instrument comprising a plurality of sensors to measure an electrical parameter |
JP5410110B2 (en) | 2008-02-14 | 2014-02-05 | エシコン・エンド−サージェリィ・インコーポレイテッド | Surgical cutting / fixing instrument with RF electrode |
US8636736B2 (en) | 2008-02-14 | 2014-01-28 | Ethicon Endo-Surgery, Inc. | Motorized surgical cutting and fastening instrument |
US8573465B2 (en) | 2008-02-14 | 2013-11-05 | Ethicon Endo-Surgery, Inc. | Robotically-controlled surgical end effector system with rotary actuated closure systems |
US9770245B2 (en) | 2008-02-15 | 2017-09-26 | Ethicon Llc | Layer arrangements for surgical staple cartridges |
WO2009139880A1 (en) * | 2008-05-13 | 2009-11-19 | Celgene Corporation | Thioxoisoindoline compounds and compositions and methods of using the same |
WO2010018846A1 (en) * | 2008-08-13 | 2010-02-18 | 協和発酵キリン株式会社 | Drug containing antibody composition specifically binding to ganglioside gm2 |
US9386983B2 (en) | 2008-09-23 | 2016-07-12 | Ethicon Endo-Surgery, Llc | Robotically-controlled motorized surgical instrument |
US8210411B2 (en) | 2008-09-23 | 2012-07-03 | Ethicon Endo-Surgery, Inc. | Motor-driven surgical cutting instrument |
US11648005B2 (en) | 2008-09-23 | 2023-05-16 | Cilag Gmbh International | Robotically-controlled motorized surgical instrument with an end effector |
US9005230B2 (en) | 2008-09-23 | 2015-04-14 | Ethicon Endo-Surgery, Inc. | Motorized surgical instrument |
US8608045B2 (en) | 2008-10-10 | 2013-12-17 | Ethicon Endo-Sugery, Inc. | Powered surgical cutting and stapling apparatus with manually retractable firing system |
AP2011005690A0 (en) | 2008-10-21 | 2011-06-30 | Onyx Therapeutics Inc | Combination therapy with peptide epoxyketones. |
US8110578B2 (en) | 2008-10-27 | 2012-02-07 | Signal Pharmaceuticals, Llc | Pyrazino[2,3-b]pyrazine mTOR kinase inhibitors for oncology indications and diseases associated with the mTOR/PI3K/Akt pathway |
SI2358697T1 (en) | 2008-10-29 | 2016-02-29 | Celgene Corporation | Isoindoline compounds for use in the treatment of cancer. |
US8623395B2 (en) | 2010-01-29 | 2014-01-07 | Forsight Vision4, Inc. | Implantable therapeutic device |
US8399006B2 (en) * | 2009-01-29 | 2013-03-19 | Forsight Vision4, Inc. | Posterior segment drug delivery |
US8517239B2 (en) | 2009-02-05 | 2013-08-27 | Ethicon Endo-Surgery, Inc. | Surgical stapling instrument comprising a magnetic element driver |
EP2393430A1 (en) | 2009-02-06 | 2011-12-14 | Ethicon Endo-Surgery, Inc. | Driven surgical stapler improvements |
WO2010093434A1 (en) | 2009-02-11 | 2010-08-19 | Celgene Corporation | Isotopologues of lenalidomide |
TWI504598B (en) | 2009-03-20 | 2015-10-21 | Onyx Therapeutics Inc | Crystalline tripeptide epoxy ketone protease inhibitors |
ES2728776T3 (en) | 2009-05-19 | 2019-10-28 | Celgene Corp | 4-amino-2- (2,6-dioxopiperidin-3-yl) isoindolin-1,3-dione formulations |
EP2436387B1 (en) | 2009-05-25 | 2018-07-25 | Celgene Corporation | Pharmaceutical composition comprising crbn for use in treating a disease of the cerebral cortex |
CN101696205B (en) | 2009-11-02 | 2011-10-19 | 南京卡文迪许生物工程技术有限公司 | 3-(substituted xylylenimine-2-yl)-2,6-dioxopiperidine polymorph and pharmaceutical composition |
JP5919196B2 (en) | 2009-11-13 | 2016-05-18 | オニキス セラピューティクス, インク.Onyx Therapeutics, Inc. | Use of peptide epoxy ketones for metastasis inhibition |
CA2780998C (en) * | 2009-11-24 | 2016-07-12 | Celgene Corporation | Immunomodulatory compounds for the restoration of vitamin d sensitivity in vitamin d resistant tumor cells |
CA2783616A1 (en) | 2009-12-22 | 2011-06-30 | Celgene Corporation | (methylsulfonyl) ethyl benzene isoindoline derivatives and their therapeutical uses |
US8851354B2 (en) | 2009-12-24 | 2014-10-07 | Ethicon Endo-Surgery, Inc. | Surgical cutting instrument that analyzes tissue thickness |
DK3284818T3 (en) * | 2010-01-26 | 2022-06-20 | Celularity Inc | Treatment of bone-related cancer using placenta stem cells |
EP4289838A3 (en) | 2010-02-11 | 2024-03-13 | Celgene Corporation | Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same |
BR112012022060A2 (en) | 2010-03-01 | 2018-05-08 | Onyx Therapeutics Inc | compound for inhibition of immunoproteasome |
JP2013522236A (en) | 2010-03-12 | 2013-06-13 | セルジーン コーポレイション | Methods for treating non-Hodgkin lymphoma using lenalidomide, and gene and protein biomarkers as predictors |
NZ602872A (en) | 2010-04-07 | 2014-05-30 | Onyx Therapeutics Inc | Crystalline peptide epoxyketone immunoproteasome inhibitor |
US8783543B2 (en) | 2010-07-30 | 2014-07-22 | Ethicon Endo-Surgery, Inc. | Tissue acquisition arrangements and methods for surgical stapling devices |
US9033911B2 (en) | 2010-08-05 | 2015-05-19 | Forsight Vision4, Inc. | Injector apparatus and method for drug delivery |
JP6111194B2 (en) | 2010-08-05 | 2017-04-05 | フォーサイト・ビジョン フォー・インコーポレーテッド | Combination drug delivery method and apparatus |
US9492315B2 (en) | 2010-08-05 | 2016-11-15 | Forsight Vision4, Inc. | Implantable therapeutic device |
WO2012027065A2 (en) * | 2010-08-27 | 2012-03-01 | Celgene Corporation | Combination therapy for treatment of disease |
US8435972B2 (en) * | 2010-09-02 | 2013-05-07 | Emory University | Method for the treatment of central nervous system cancers and compositions related thereto |
US11298125B2 (en) | 2010-09-30 | 2022-04-12 | Cilag Gmbh International | Tissue stapler having a thickness compensator |
US9320523B2 (en) | 2012-03-28 | 2016-04-26 | Ethicon Endo-Surgery, Llc | Tissue thickness compensator comprising tissue ingrowth features |
US11849952B2 (en) | 2010-09-30 | 2023-12-26 | Cilag Gmbh International | Staple cartridge comprising staples positioned within a compressible portion thereof |
US10213198B2 (en) | 2010-09-30 | 2019-02-26 | Ethicon Llc | Actuator for releasing a tissue thickness compensator from a fastener cartridge |
US9168038B2 (en) | 2010-09-30 | 2015-10-27 | Ethicon Endo-Surgery, Inc. | Staple cartridge comprising a tissue thickness compensator |
US11812965B2 (en) | 2010-09-30 | 2023-11-14 | Cilag Gmbh International | Layer of material for a surgical end effector |
US9629814B2 (en) | 2010-09-30 | 2017-04-25 | Ethicon Endo-Surgery, Llc | Tissue thickness compensator configured to redistribute compressive forces |
US10945731B2 (en) | 2010-09-30 | 2021-03-16 | Ethicon Llc | Tissue thickness compensator comprising controlled release and expansion |
US9839420B2 (en) | 2010-09-30 | 2017-12-12 | Ethicon Llc | Tissue thickness compensator comprising at least one medicament |
US8695866B2 (en) | 2010-10-01 | 2014-04-15 | Ethicon Endo-Surgery, Inc. | Surgical instrument having a power control circuit |
US20140031769A1 (en) | 2010-11-19 | 2014-01-30 | Forsight Vision4, Inc. | Therapeutic agent formulations for implanted devices |
AR083957A1 (en) | 2010-11-22 | 2013-04-10 | Innate Pharma Sa | TREATMENT TO MODULATE NK CELLS AND METHODS TO TREAT HEMATOLOGICAL MALIGNITY |
US8853175B2 (en) | 2011-01-10 | 2014-10-07 | Celgene Corporation | Phenethylsulfone isoindoline derivatives and their use |
PE20140983A1 (en) | 2011-03-11 | 2014-08-25 | Celgene Corp | SOLID FORMS OF 3- (5-AMINO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-IL) -PIPERIDIN-2,6-DIONA, AND ITS PHARMACEUTICAL COMPOSITIONS AND ITS USES |
HUE027481T2 (en) | 2011-03-11 | 2016-09-28 | Celgene Corp | Methods of treating cancer using 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione |
US9090585B2 (en) | 2011-03-28 | 2015-07-28 | Deuterx, Llc | 2,6-dioxo-3-deutero-piperdin-3-yl-isoindoline compounds |
MX2013012083A (en) * | 2011-04-18 | 2014-04-16 | Celgene Corp | Biomarkers for the treatment of multiple myeloma. |
JP6026509B2 (en) | 2011-04-29 | 2016-11-16 | エシコン・エンド−サージェリィ・インコーポレイテッドEthicon Endo−Surgery,Inc. | Staple cartridge including staples disposed within a compressible portion of the staple cartridge itself |
KR20140024914A (en) | 2011-04-29 | 2014-03-03 | 셀진 코포레이션 | Methods for the treatment of cancer and inflammatory diseases using cereblon as a predictor |
US11207064B2 (en) | 2011-05-27 | 2021-12-28 | Cilag Gmbh International | Automated end effector component reloading system for use with a robotic system |
US20140221427A1 (en) | 2011-06-22 | 2014-08-07 | Celgene Corporation | Isotopologues of pomalidomide |
US10398592B2 (en) | 2011-06-28 | 2019-09-03 | Forsight Vision4, Inc. | Diagnostic methods and apparatus |
EP2739252A4 (en) | 2011-08-05 | 2015-08-12 | Forsight Vision4 Inc | Small molecule delivery with implantable therapeutic device |
MX356105B (en) | 2011-09-14 | 2018-05-14 | Celgene Corp | Formulations of cyclopropanecarboxylic acid {2-(1s)-1-(3-ethoxy-4 -methoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1h-i soindol-4-yl}-amidecelgene corporation state of incorporation:delaware. |
PT2755600T (en) | 2011-09-16 | 2021-04-19 | Forsight Vision4 Inc | Fluid exchange apparatus and methods |
WO2013052803A2 (en) * | 2011-10-07 | 2013-04-11 | Radiorx, Inc. | Methods and compositions comprising a nitrite-reductase promoter for treatment of medical disorders and preservation of blood products |
HUE050327T2 (en) | 2011-12-27 | 2020-11-30 | Amgen Europe Gmbh | Formulations of (+)-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-4-acetyl aminoisoindoline-1,3-dione |
EP2817300B1 (en) | 2012-02-21 | 2018-04-25 | Celgene Corporation | Solid forms of 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione |
CN104334098B (en) | 2012-03-28 | 2017-03-22 | 伊西康内外科公司 | Tissue thickness compensator comprising capsules defining a low pressure environment |
RU2644272C2 (en) | 2012-03-28 | 2018-02-08 | Этикон Эндо-Серджери, Инк. | Limitation node with tissue thickness compensator |
WO2013148219A1 (en) | 2012-03-28 | 2013-10-03 | University Of Central Florida Research Foundation, Inc. | Anti-metatstatic agents predicated upon polyamine-macrocyclic conjugates |
MX358135B (en) | 2012-03-28 | 2018-08-06 | Ethicon Endo Surgery Inc | Tissue thickness compensator comprising a plurality of layers. |
WO2013148230A1 (en) | 2012-03-28 | 2013-10-03 | University Of Central Florida Research Foundation, Inc. | Polyamine transport selective therapeutic agents with enhanced stability |
US9101358B2 (en) | 2012-06-15 | 2015-08-11 | Ethicon Endo-Surgery, Inc. | Articulatable surgical instrument comprising a firing drive |
US20140001231A1 (en) | 2012-06-28 | 2014-01-02 | Ethicon Endo-Surgery, Inc. | Firing system lockout arrangements for surgical instruments |
US9364230B2 (en) | 2012-06-28 | 2016-06-14 | Ethicon Endo-Surgery, Llc | Surgical stapling instruments with rotary joint assemblies |
US11278284B2 (en) | 2012-06-28 | 2022-03-22 | Cilag Gmbh International | Rotary drive arrangements for surgical instruments |
BR112014032776B1 (en) | 2012-06-28 | 2021-09-08 | Ethicon Endo-Surgery, Inc | SURGICAL INSTRUMENT SYSTEM AND SURGICAL KIT FOR USE WITH A SURGICAL INSTRUMENT SYSTEM |
US9289256B2 (en) | 2012-06-28 | 2016-03-22 | Ethicon Endo-Surgery, Llc | Surgical end effectors having angled tissue-contacting surfaces |
US9282974B2 (en) | 2012-06-28 | 2016-03-15 | Ethicon Endo-Surgery, Llc | Empty clip cartridge lockout |
RU2636861C2 (en) | 2012-06-28 | 2017-11-28 | Этикон Эндо-Серджери, Инк. | Blocking of empty cassette with clips |
ES2872967T3 (en) | 2012-06-29 | 2021-11-03 | Celgene Corp | Methods to determine drug efficacy using IKZF3 (AIOLOS) |
JP2015524394A (en) | 2012-07-09 | 2015-08-24 | オニキス セラピューティクス, インク.Onyx Therapeutics, Inc. | Prodrugs of peptide epoxyketone protease inhibitors |
PL2882442T3 (en) | 2012-08-09 | 2021-12-13 | Celgene Corporation | Methods of treating cancer using 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione |
US9587281B2 (en) | 2012-08-14 | 2017-03-07 | Celgene Corporation | Cereblon isoforms and their use as biomarkers for therapeutic treatment |
EA201590535A1 (en) | 2012-09-10 | 2015-07-30 | Селджин Корпорейшн | METHODS OF TREATMENT OF LOCALLY PROGRESSIVE RUNNING BREAST CANCER |
US20150297579A1 (en) * | 2012-11-05 | 2015-10-22 | Celgene Corporation | Treatment of cancer with pomalidomide in a renally impaired subject |
US10342869B2 (en) * | 2012-12-07 | 2019-07-09 | The Regents Of The University Of California | Compositions comprising anti-CD38 antibodies and lenalidomide |
WO2014110558A1 (en) | 2013-01-14 | 2014-07-17 | Deuterx, Llc | 3-(5-substituted-4-oxoquinazolin-3(4h)-yl)-3-deutero-piperidine-2,6-dione derivatives |
EP2764866A1 (en) | 2013-02-07 | 2014-08-13 | IP Gesellschaft für Management mbH | Inhibitors of nedd8-activating enzyme |
BR112015021082B1 (en) | 2013-03-01 | 2022-05-10 | Ethicon Endo-Surgery, Inc | surgical instrument |
JP6382235B2 (en) | 2013-03-01 | 2018-08-29 | エシコン・エンド−サージェリィ・インコーポレイテッドEthicon Endo−Surgery,Inc. | Articulatable surgical instrument with a conductive path for signal communication |
US9629629B2 (en) | 2013-03-14 | 2017-04-25 | Ethicon Endo-Surgey, LLC | Control systems for surgical instruments |
US9629623B2 (en) | 2013-03-14 | 2017-04-25 | Ethicon Endo-Surgery, Llc | Drive system lockout arrangements for modular surgical instruments |
EP2968113B8 (en) | 2013-03-14 | 2020-10-28 | Forsight Vision4, Inc. | Systems for sustained intraocular delivery of low solubility compounds from a port delivery system implant |
ES2972168T3 (en) | 2013-03-28 | 2024-06-11 | Forsight Vision4 Inc | Ophthalmic implant for administration of therapeutic substances |
MX2015013912A (en) | 2013-04-02 | 2016-08-12 | Celgene Corp | Methods and compositions using 4-amino-2-(2,6-dioxo-piperidine-3- yl)-isoindoline-1,3-dione for treatment and management of central nervous system cancers. |
US10136887B2 (en) | 2013-04-16 | 2018-11-27 | Ethicon Llc | Drive system decoupling arrangement for a surgical instrument |
BR112015026109B1 (en) | 2013-04-16 | 2022-02-22 | Ethicon Endo-Surgery, Inc | surgical instrument |
EP2815749A1 (en) | 2013-06-20 | 2014-12-24 | IP Gesellschaft für Management mbH | Solid form of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione having specified X-ray diffraction pattern |
US9808249B2 (en) | 2013-08-23 | 2017-11-07 | Ethicon Llc | Attachment portions for surgical instrument assemblies |
RU2678363C2 (en) | 2013-08-23 | 2019-01-28 | ЭТИКОН ЭНДО-СЕРДЖЕРИ, ЭлЭлСи | Firing member retraction devices for powered surgical instruments |
US9492471B2 (en) | 2013-08-27 | 2016-11-15 | Celgene Avilomics Research, Inc. | Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase |
SG11201602791RA (en) * | 2013-10-11 | 2016-05-30 | Acetylon Pharmaceuticals Inc | Combinations of histone deactylase inhibitors and immunomodulatory drugs |
US20150139979A1 (en) * | 2013-11-19 | 2015-05-21 | Celgene Avilomics Research, Inc. | Methods of treating a disease or disorder associated with bruton's tyrosine kinase |
JP6535670B2 (en) * | 2013-12-03 | 2019-06-26 | アセチロン ファーマシューティカルズ インコーポレイテッドAcetylon Pharmaceuticals,Inc. | Combination of histone deacetylase inhibitors and immunomodulators |
WO2015085172A2 (en) | 2013-12-06 | 2015-06-11 | Celgene Corporation | Methods for determining drug efficacy for the treatment of diffuse large b-cell lymphoma, multiple myeloma, and myeloid cancers |
WO2015116802A1 (en) | 2014-01-29 | 2015-08-06 | Otsuka Pharmaceutical Co., Ltd. | Device-based risk management of a therapeutic |
US9962161B2 (en) | 2014-02-12 | 2018-05-08 | Ethicon Llc | Deliverable surgical instrument |
US9804618B2 (en) | 2014-03-26 | 2017-10-31 | Ethicon Llc | Systems and methods for controlling a segmented circuit |
US20150272557A1 (en) | 2014-03-26 | 2015-10-01 | Ethicon Endo-Surgery, Inc. | Modular surgical instrument system |
BR112016021943B1 (en) | 2014-03-26 | 2022-06-14 | Ethicon Endo-Surgery, Llc | SURGICAL INSTRUMENT FOR USE BY AN OPERATOR IN A SURGICAL PROCEDURE |
CN106659765B (en) | 2014-04-04 | 2021-08-13 | 德玛医药 | Use of dianhydrogalactitol and analogs or derivatives thereof for treating non-small cell lung cancer and ovarian cancer |
BR112016023698B1 (en) | 2014-04-16 | 2022-07-26 | Ethicon Endo-Surgery, Llc | FASTENER CARTRIDGE FOR USE WITH A SURGICAL INSTRUMENT |
US20150297225A1 (en) | 2014-04-16 | 2015-10-22 | Ethicon Endo-Surgery, Inc. | Fastener cartridges including extensions having different configurations |
US10470768B2 (en) | 2014-04-16 | 2019-11-12 | Ethicon Llc | Fastener cartridge including a layer attached thereto |
US10206677B2 (en) | 2014-09-26 | 2019-02-19 | Ethicon Llc | Surgical staple and driver arrangements for staple cartridges |
BR112016023807B1 (en) | 2014-04-16 | 2022-07-12 | Ethicon Endo-Surgery, Llc | CARTRIDGE SET OF FASTENERS FOR USE WITH A SURGICAL INSTRUMENT |
CN106456158B (en) | 2014-04-16 | 2019-02-05 | 伊西康内外科有限责任公司 | Fastener cartridge including non-uniform fastener |
EP3160486B1 (en) | 2014-06-27 | 2020-11-18 | Celgene Corporation | Compositions and methods for inducing conformational changes in cereblon other e3 ubiquitin ligases |
US9499514B2 (en) | 2014-07-11 | 2016-11-22 | Celgene Corporation | Antiproliferative compounds and methods of use thereof |
MY182793A (en) | 2014-08-08 | 2021-02-05 | Forsight Vision4 Inc | Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof |
SI3186241T1 (en) | 2014-08-29 | 2021-03-31 | Chdi Foundation, Inc. | Probes for imaging huntington protein |
US9757128B2 (en) | 2014-09-05 | 2017-09-12 | Ethicon Llc | Multiple sensors with one sensor affecting a second sensor's output or interpretation |
US11311294B2 (en) | 2014-09-05 | 2022-04-26 | Cilag Gmbh International | Powered medical device including measurement of closure state of jaws |
BR112017004361B1 (en) | 2014-09-05 | 2023-04-11 | Ethicon Llc | ELECTRONIC SYSTEM FOR A SURGICAL INSTRUMENT |
US10105142B2 (en) | 2014-09-18 | 2018-10-23 | Ethicon Llc | Surgical stapler with plurality of cutting elements |
BR112017005981B1 (en) | 2014-09-26 | 2022-09-06 | Ethicon, Llc | ANCHOR MATERIAL FOR USE WITH A SURGICAL STAPLE CARTRIDGE AND SURGICAL STAPLE CARTRIDGE FOR USE WITH A SURGICAL INSTRUMENT |
US11523821B2 (en) | 2014-09-26 | 2022-12-13 | Cilag Gmbh International | Method for creating a flexible staple line |
US9924944B2 (en) | 2014-10-16 | 2018-03-27 | Ethicon Llc | Staple cartridge comprising an adjunct material |
US11141153B2 (en) | 2014-10-29 | 2021-10-12 | Cilag Gmbh International | Staple cartridges comprising driver arrangements |
US10517594B2 (en) | 2014-10-29 | 2019-12-31 | Ethicon Llc | Cartridge assemblies for surgical staplers |
US9844376B2 (en) | 2014-11-06 | 2017-12-19 | Ethicon Llc | Staple cartridge comprising a releasable adjunct material |
US10736636B2 (en) | 2014-12-10 | 2020-08-11 | Ethicon Llc | Articulatable surgical instrument system |
US9844374B2 (en) | 2014-12-18 | 2017-12-19 | Ethicon Llc | Surgical instrument systems comprising an articulatable end effector and means for adjusting the firing stroke of a firing member |
US9844375B2 (en) | 2014-12-18 | 2017-12-19 | Ethicon Llc | Drive arrangements for articulatable surgical instruments |
US10085748B2 (en) | 2014-12-18 | 2018-10-02 | Ethicon Llc | Locking arrangements for detachable shaft assemblies with articulatable surgical end effectors |
US9987000B2 (en) | 2014-12-18 | 2018-06-05 | Ethicon Llc | Surgical instrument assembly comprising a flexible articulation system |
US9968355B2 (en) | 2014-12-18 | 2018-05-15 | Ethicon Llc | Surgical instruments with articulatable end effectors and improved firing beam support arrangements |
MX2017008108A (en) | 2014-12-18 | 2018-03-06 | Ethicon Llc | Surgical instrument with an anvil that is selectively movable about a discrete non-movable axis relative to a staple cartridge. |
US11154301B2 (en) | 2015-02-27 | 2021-10-26 | Cilag Gmbh International | Modular stapling assembly |
US10245033B2 (en) | 2015-03-06 | 2019-04-02 | Ethicon Llc | Surgical instrument comprising a lockable battery housing |
US9901342B2 (en) | 2015-03-06 | 2018-02-27 | Ethicon Endo-Surgery, Llc | Signal and power communication system positioned on a rotatable shaft |
US10441279B2 (en) | 2015-03-06 | 2019-10-15 | Ethicon Llc | Multiple level thresholds to modify operation of powered surgical instruments |
US9993248B2 (en) | 2015-03-06 | 2018-06-12 | Ethicon Endo-Surgery, Llc | Smart sensors with local signal processing |
JP2020121162A (en) | 2015-03-06 | 2020-08-13 | エシコン エルエルシーEthicon LLC | Time dependent evaluation of sensor data to determine stability element, creep element and viscoelastic element of measurement |
US10052044B2 (en) | 2015-03-06 | 2018-08-21 | Ethicon Llc | Time dependent evaluation of sensor data to determine stability, creep, and viscoelastic elements of measures |
US10213201B2 (en) | 2015-03-31 | 2019-02-26 | Ethicon Llc | Stapling end effector configured to compensate for an uneven gap between a first jaw and a second jaw |
SI3313818T1 (en) | 2015-06-26 | 2024-03-29 | Celgene Corporation | Methods for the treatment of kaposi's sarcoma or kshv-induced lymphoma using immunomodulatory compounds, and uses of biomarkers |
SI3313528T1 (en) | 2015-06-29 | 2021-11-30 | Bristol-Myers Squibb Company | Immunotherapeutic dosing regimens comprising pomalidomide and an anti-cs1 antibody for treating cancer |
US11058425B2 (en) | 2015-08-17 | 2021-07-13 | Ethicon Llc | Implantable layers for a surgical instrument |
PT3640345T (en) | 2015-08-17 | 2021-12-29 | Kura Oncology Inc | Methods of treating cancer patients with farnesyl transferase inhibitors |
US10105139B2 (en) | 2015-09-23 | 2018-10-23 | Ethicon Llc | Surgical stapler having downstream current-based motor control |
US10238386B2 (en) | 2015-09-23 | 2019-03-26 | Ethicon Llc | Surgical stapler having motor control based on an electrical parameter related to a motor current |
US10299878B2 (en) | 2015-09-25 | 2019-05-28 | Ethicon Llc | Implantable adjunct systems for determining adjunct skew |
US10980539B2 (en) | 2015-09-30 | 2021-04-20 | Ethicon Llc | Implantable adjunct comprising bonded layers |
US10524788B2 (en) | 2015-09-30 | 2020-01-07 | Ethicon Llc | Compressible adjunct with attachment regions |
US10736633B2 (en) | 2015-09-30 | 2020-08-11 | Ethicon Llc | Compressible adjunct with looping members |
US11890015B2 (en) | 2015-09-30 | 2024-02-06 | Cilag Gmbh International | Compressible adjunct with crossing spacer fibers |
US10342778B1 (en) | 2015-10-20 | 2019-07-09 | Epicentrx, Inc. | Treatment of brain metastases using organonitro compound combination therapy |
US9987270B1 (en) | 2015-10-29 | 2018-06-05 | Epicentrix, Inc. | Treatment of gliomas using organonitro compound combination therapy |
MX2018006234A (en) | 2015-11-20 | 2018-08-14 | Forsight Vision4 Inc | Porous structures for extended release drug delivery devices. |
CA3006758A1 (en) | 2015-12-02 | 2017-06-08 | Celgene Corporation | Cycling therapy using 3-(5-amino-2-methyl-4-oxo-4h-quinazolin-3-yl)-piperidine-2,6-dione |
WO2017117118A1 (en) | 2015-12-28 | 2017-07-06 | Celgene Corporation | Compositions and methods for inducing conformational changes in cereblon and other e3 ubiquitin ligases |
US10292704B2 (en) | 2015-12-30 | 2019-05-21 | Ethicon Llc | Mechanisms for compensating for battery pack failure in powered surgical instruments |
US10265068B2 (en) | 2015-12-30 | 2019-04-23 | Ethicon Llc | Surgical instruments with separable motors and motor control circuits |
US10368865B2 (en) | 2015-12-30 | 2019-08-06 | Ethicon Llc | Mechanisms for compensating for drivetrain failure in powered surgical instruments |
MX367669B (en) * | 2016-01-08 | 2019-08-30 | Celgene Corp | Antiproliferative compounds, and their pharmaceutical compositions and uses. |
DK3402480T3 (en) | 2016-01-11 | 2021-06-28 | Epicentrx Inc | COMPOSITIONS AND PROCEDURES FOR INTRAVENOUS ADMINISTRATION OF 2-BROMO-1- (3,3-DINITROAZETIDIN-1-YL) ETHANONE |
US11213293B2 (en) | 2016-02-09 | 2022-01-04 | Cilag Gmbh International | Articulatable surgical instruments with single articulation link arrangements |
BR112018016098B1 (en) | 2016-02-09 | 2023-02-23 | Ethicon Llc | SURGICAL INSTRUMENT |
US11224426B2 (en) | 2016-02-12 | 2022-01-18 | Cilag Gmbh International | Mechanisms for compensating for drivetrain failure in powered surgical instruments |
US10448948B2 (en) | 2016-02-12 | 2019-10-22 | Ethicon Llc | Mechanisms for compensating for drivetrain failure in powered surgical instruments |
US10426467B2 (en) | 2016-04-15 | 2019-10-01 | Ethicon Llc | Surgical instrument with detection sensors |
US10335145B2 (en) | 2016-04-15 | 2019-07-02 | Ethicon Llc | Modular surgical instrument with configurable operating mode |
US11179150B2 (en) | 2016-04-15 | 2021-11-23 | Cilag Gmbh International | Systems and methods for controlling a surgical stapling and cutting instrument |
US10828028B2 (en) | 2016-04-15 | 2020-11-10 | Ethicon Llc | Surgical instrument with multiple program responses during a firing motion |
US11607239B2 (en) | 2016-04-15 | 2023-03-21 | Cilag Gmbh International | Systems and methods for controlling a surgical stapling and cutting instrument |
US10357247B2 (en) | 2016-04-15 | 2019-07-23 | Ethicon Llc | Surgical instrument with multiple program responses during a firing motion |
US10492783B2 (en) | 2016-04-15 | 2019-12-03 | Ethicon, Llc | Surgical instrument with improved stop/start control during a firing motion |
US10456137B2 (en) | 2016-04-15 | 2019-10-29 | Ethicon Llc | Staple formation detection mechanisms |
US11317917B2 (en) | 2016-04-18 | 2022-05-03 | Cilag Gmbh International | Surgical stapling system comprising a lockable firing assembly |
US10368867B2 (en) | 2016-04-18 | 2019-08-06 | Ethicon Llc | Surgical instrument comprising a lockout |
US20170296173A1 (en) | 2016-04-18 | 2017-10-19 | Ethicon Endo-Surgery, Llc | Method for operating a surgical instrument |
SG11201903312VA (en) | 2016-10-14 | 2019-05-30 | Epicentrix Inc | Sulfoxyalkyl organonitro and related compounds and pharmaceutical compositions for use in medicine |
DK3534885T3 (en) | 2016-11-03 | 2021-04-12 | Kura Oncology Inc | FARNESYLTRANSFERASE INHIBITORS FOR USE IN CANCER OF CANCER |
US11134942B2 (en) | 2016-12-21 | 2021-10-05 | Cilag Gmbh International | Surgical stapling instruments and staple-forming anvils |
US10542982B2 (en) | 2016-12-21 | 2020-01-28 | Ethicon Llc | Shaft assembly comprising first and second articulation lockouts |
US10568624B2 (en) | 2016-12-21 | 2020-02-25 | Ethicon Llc | Surgical instruments with jaws that are pivotable about a fixed axis and include separate and distinct closure and firing systems |
US10524789B2 (en) | 2016-12-21 | 2020-01-07 | Ethicon Llc | Laterally actuatable articulation lock arrangements for locking an end effector of a surgical instrument in an articulated configuration |
US11090048B2 (en) | 2016-12-21 | 2021-08-17 | Cilag Gmbh International | Method for resetting a fuse of a surgical instrument shaft |
US10856868B2 (en) | 2016-12-21 | 2020-12-08 | Ethicon Llc | Firing member pin configurations |
US20180168615A1 (en) | 2016-12-21 | 2018-06-21 | Ethicon Endo-Surgery, Llc | Method of deforming staples from two different types of staple cartridges with the same surgical stapling instrument |
CN110099619B (en) | 2016-12-21 | 2022-07-15 | 爱惜康有限责任公司 | Lockout device for surgical end effector and replaceable tool assembly |
US11419606B2 (en) | 2016-12-21 | 2022-08-23 | Cilag Gmbh International | Shaft assembly comprising a clutch configured to adapt the output of a rotary firing member to two different systems |
US10624635B2 (en) | 2016-12-21 | 2020-04-21 | Ethicon Llc | Firing members with non-parallel jaw engagement features for surgical end effectors |
US20180168625A1 (en) | 2016-12-21 | 2018-06-21 | Ethicon Endo-Surgery, Llc | Surgical stapling instruments with smart staple cartridges |
MX2019007295A (en) | 2016-12-21 | 2019-10-15 | Ethicon Llc | Surgical instrument system comprising an end effector lockout and a firing assembly lockout. |
JP7010956B2 (en) | 2016-12-21 | 2022-01-26 | エシコン エルエルシー | How to staple tissue |
US10568625B2 (en) | 2016-12-21 | 2020-02-25 | Ethicon Llc | Staple cartridges and arrangements of staples and staple cavities therein |
US10639035B2 (en) | 2016-12-21 | 2020-05-05 | Ethicon Llc | Surgical stapling instruments and replaceable tool assemblies thereof |
US10499914B2 (en) | 2016-12-21 | 2019-12-10 | Ethicon Llc | Staple forming pocket arrangements |
BR112019011947A2 (en) | 2016-12-21 | 2019-10-29 | Ethicon Llc | surgical stapling systems |
WO2018125968A1 (en) * | 2016-12-28 | 2018-07-05 | Emory University | Glut4 selective inhibitors for cancer therapy |
US11034667B2 (en) | 2017-01-09 | 2021-06-15 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
US11584733B2 (en) | 2017-01-09 | 2023-02-21 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
US10093647B1 (en) | 2017-05-26 | 2018-10-09 | Celgene Corporation | Crystalline 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione dihydrate, compositions and methods of use thereof |
US11071554B2 (en) | 2017-06-20 | 2021-07-27 | Cilag Gmbh International | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on magnitude of velocity error measurements |
US11382638B2 (en) | 2017-06-20 | 2022-07-12 | Cilag Gmbh International | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured time over a specified displacement distance |
US10779820B2 (en) | 2017-06-20 | 2020-09-22 | Ethicon Llc | Systems and methods for controlling motor speed according to user input for a surgical instrument |
US11090046B2 (en) | 2017-06-20 | 2021-08-17 | Cilag Gmbh International | Systems and methods for controlling displacement member motion of a surgical stapling and cutting instrument |
US11517325B2 (en) | 2017-06-20 | 2022-12-06 | Cilag Gmbh International | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured displacement distance traveled over a specified time interval |
US10888321B2 (en) | 2017-06-20 | 2021-01-12 | Ethicon Llc | Systems and methods for controlling velocity of a displacement member of a surgical stapling and cutting instrument |
US10881399B2 (en) | 2017-06-20 | 2021-01-05 | Ethicon Llc | Techniques for adaptive control of motor velocity of a surgical stapling and cutting instrument |
US10307170B2 (en) | 2017-06-20 | 2019-06-04 | Ethicon Llc | Method for closed loop control of motor velocity of a surgical stapling and cutting instrument |
US10980537B2 (en) | 2017-06-20 | 2021-04-20 | Ethicon Llc | Closed loop feedback control of motor velocity of a surgical stapling and cutting instrument based on measured time over a specified number of shaft rotations |
US11653914B2 (en) | 2017-06-20 | 2023-05-23 | Cilag Gmbh International | Systems and methods for controlling motor velocity of a surgical stapling and cutting instrument according to articulation angle of end effector |
US10993716B2 (en) | 2017-06-27 | 2021-05-04 | Ethicon Llc | Surgical anvil arrangements |
US11324503B2 (en) | 2017-06-27 | 2022-05-10 | Cilag Gmbh International | Surgical firing member arrangements |
US11141154B2 (en) | 2017-06-27 | 2021-10-12 | Cilag Gmbh International | Surgical end effectors and anvils |
US11266405B2 (en) | 2017-06-27 | 2022-03-08 | Cilag Gmbh International | Surgical anvil manufacturing methods |
EP3420947B1 (en) | 2017-06-28 | 2022-05-25 | Cilag GmbH International | Surgical instrument comprising selectively actuatable rotatable couplers |
US11259805B2 (en) | 2017-06-28 | 2022-03-01 | Cilag Gmbh International | Surgical instrument comprising firing member supports |
US10903685B2 (en) | 2017-06-28 | 2021-01-26 | Ethicon Llc | Surgical shaft assemblies with slip ring assemblies forming capacitive channels |
US20190000459A1 (en) | 2017-06-28 | 2019-01-03 | Ethicon Llc | Surgical instruments with jaws constrained to pivot about an axis upon contact with a closure member that is parked in close proximity to the pivot axis |
US11246592B2 (en) | 2017-06-28 | 2022-02-15 | Cilag Gmbh International | Surgical instrument comprising an articulation system lockable to a frame |
USD906355S1 (en) | 2017-06-28 | 2020-12-29 | Ethicon Llc | Display screen or portion thereof with a graphical user interface for a surgical instrument |
US11389161B2 (en) | 2017-06-28 | 2022-07-19 | Cilag Gmbh International | Surgical instrument comprising selectively actuatable rotatable couplers |
US10765427B2 (en) | 2017-06-28 | 2020-09-08 | Ethicon Llc | Method for articulating a surgical instrument |
US11564686B2 (en) | 2017-06-28 | 2023-01-31 | Cilag Gmbh International | Surgical shaft assemblies with flexible interfaces |
US10932772B2 (en) | 2017-06-29 | 2021-03-02 | Ethicon Llc | Methods for closed loop velocity control for robotic surgical instrument |
BR112020000196A2 (en) | 2017-07-07 | 2020-07-07 | Epicentrx, Inc. | compositions for parenteral administration of therapeutic agents |
US11944300B2 (en) | 2017-08-03 | 2024-04-02 | Cilag Gmbh International | Method for operating a surgical system bailout |
US11471155B2 (en) | 2017-08-03 | 2022-10-18 | Cilag Gmbh International | Surgical system bailout |
US11304695B2 (en) | 2017-08-03 | 2022-04-19 | Cilag Gmbh International | Surgical system shaft interconnection |
US11974742B2 (en) | 2017-08-03 | 2024-05-07 | Cilag Gmbh International | Surgical system comprising an articulation bailout |
CN111107874A (en) | 2017-09-14 | 2020-05-05 | 葛兰素史密斯克莱知识产权发展有限公司 | Combination therapy for cancer |
US10093649B1 (en) | 2017-09-22 | 2018-10-09 | Celgene Corporation | Crystalline 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione monohydrate, compositions and methods of use thereof |
US10093648B1 (en) | 2017-09-22 | 2018-10-09 | Celgene Corporation | Crystalline 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione hemihydrate, compositions and methods of use thereof |
US11399829B2 (en) | 2017-09-29 | 2022-08-02 | Cilag Gmbh International | Systems and methods of initiating a power shutdown mode for a surgical instrument |
USD917500S1 (en) | 2017-09-29 | 2021-04-27 | Ethicon Llc | Display screen or portion thereof with graphical user interface |
USD907647S1 (en) | 2017-09-29 | 2021-01-12 | Ethicon Llc | Display screen or portion thereof with animated graphical user interface |
USD907648S1 (en) | 2017-09-29 | 2021-01-12 | Ethicon Llc | Display screen or portion thereof with animated graphical user interface |
US10743872B2 (en) | 2017-09-29 | 2020-08-18 | Ethicon Llc | System and methods for controlling a display of a surgical instrument |
US11505560B2 (en) | 2017-10-20 | 2022-11-22 | Dana-Farber Cancer Institute, Inc. | Heterobifunctional compounds with improved specificity |
AU2018356008A1 (en) * | 2017-10-26 | 2020-05-14 | Ulrich JENTSCHURA | Combination therapy containing immune boosters, digestive enzymes and inteferons for cancer treatment |
US11090075B2 (en) | 2017-10-30 | 2021-08-17 | Cilag Gmbh International | Articulation features for surgical end effector |
US11134944B2 (en) | 2017-10-30 | 2021-10-05 | Cilag Gmbh International | Surgical stapler knife motion controls |
US10842490B2 (en) | 2017-10-31 | 2020-11-24 | Ethicon Llc | Cartridge body design with force reduction based on firing completion |
CN111372585A (en) | 2017-11-16 | 2020-07-03 | C4医药公司 | Degradants and degreddeterminants for target protein degradation |
BR112020010053A2 (en) | 2017-11-21 | 2020-11-03 | Forsight Vision4, Inc. | fluid change device for expandable door release system and methods of using it |
WO2019113269A1 (en) | 2017-12-08 | 2019-06-13 | Kura Oncology, Inc. | Methods of treating cancer patients with farnesyltransferase inhibitors |
US11071543B2 (en) | 2017-12-15 | 2021-07-27 | Cilag Gmbh International | Surgical end effectors with clamping assemblies configured to increase jaw aperture ranges |
US11033267B2 (en) | 2017-12-15 | 2021-06-15 | Ethicon Llc | Systems and methods of controlling a clamping member firing rate of a surgical instrument |
US10869666B2 (en) | 2017-12-15 | 2020-12-22 | Ethicon Llc | Adapters with control systems for controlling multiple motors of an electromechanical surgical instrument |
US10828033B2 (en) | 2017-12-15 | 2020-11-10 | Ethicon Llc | Handheld electromechanical surgical instruments with improved motor control arrangements for positioning components of an adapter coupled thereto |
US10779826B2 (en) | 2017-12-15 | 2020-09-22 | Ethicon Llc | Methods of operating surgical end effectors |
US10779825B2 (en) | 2017-12-15 | 2020-09-22 | Ethicon Llc | Adapters with end effector position sensing and control arrangements for use in connection with electromechanical surgical instruments |
US10966718B2 (en) | 2017-12-15 | 2021-04-06 | Ethicon Llc | Dynamic clamping assemblies with improved wear characteristics for use in connection with electromechanical surgical instruments |
US11197670B2 (en) | 2017-12-15 | 2021-12-14 | Cilag Gmbh International | Surgical end effectors with pivotal jaws configured to touch at their respective distal ends when fully closed |
US10537585B2 (en) | 2017-12-18 | 2020-01-21 | Dexcel Pharma Technologies Ltd. | Compositions comprising dexamethasone |
US11020112B2 (en) | 2017-12-19 | 2021-06-01 | Ethicon Llc | Surgical tools configured for interchangeable use with different controller interfaces |
US10835330B2 (en) | 2017-12-19 | 2020-11-17 | Ethicon Llc | Method for determining the position of a rotatable jaw of a surgical instrument attachment assembly |
USD910847S1 (en) | 2017-12-19 | 2021-02-16 | Ethicon Llc | Surgical instrument assembly |
US11311290B2 (en) | 2017-12-21 | 2022-04-26 | Cilag Gmbh International | Surgical instrument comprising an end effector dampener |
US11129680B2 (en) | 2017-12-21 | 2021-09-28 | Cilag Gmbh International | Surgical instrument comprising a projector |
US11337691B2 (en) | 2017-12-21 | 2022-05-24 | Cilag Gmbh International | Surgical instrument configured to determine firing path |
US11076853B2 (en) | 2017-12-21 | 2021-08-03 | Cilag Gmbh International | Systems and methods of displaying a knife position during transection for a surgical instrument |
CA3086710A1 (en) * | 2017-12-21 | 2019-06-27 | The Angiogenesis Foundation | Compositions and methods for treating neoplasia |
US11510901B2 (en) | 2018-01-08 | 2022-11-29 | Epicentrx, Inc. | Methods and compositions utilizing RRx-001 combination therapy for radioprotection |
CA3087565A1 (en) | 2018-01-09 | 2019-07-18 | Shuttle Pharmaceuticals, Inc. | Selective histone deacetylase inhibitors for the treatment of human disease |
CA3090275A1 (en) | 2018-02-14 | 2019-08-22 | Dana-Farber Cancer Institute, Inc. | Irak degraders and uses thereof |
WO2019191112A1 (en) | 2018-03-26 | 2019-10-03 | C4 Therapeutics, Inc. | Cereblon binders for the degradation of ikaros |
EP3781156A4 (en) | 2018-04-16 | 2022-05-18 | C4 Therapeutics, Inc. | Spirocyclic compounds |
USD914878S1 (en) | 2018-08-20 | 2021-03-30 | Ethicon Llc | Surgical instrument anvil |
US11045192B2 (en) | 2018-08-20 | 2021-06-29 | Cilag Gmbh International | Fabricating techniques for surgical stapler anvils |
US11291440B2 (en) | 2018-08-20 | 2022-04-05 | Cilag Gmbh International | Method for operating a powered articulatable surgical instrument |
US11083458B2 (en) | 2018-08-20 | 2021-08-10 | Cilag Gmbh International | Powered surgical instruments with clutching arrangements to convert linear drive motions to rotary drive motions |
US11039834B2 (en) | 2018-08-20 | 2021-06-22 | Cilag Gmbh International | Surgical stapler anvils with staple directing protrusions and tissue stability features |
US11324501B2 (en) | 2018-08-20 | 2022-05-10 | Cilag Gmbh International | Surgical stapling devices with improved closure members |
US11207065B2 (en) | 2018-08-20 | 2021-12-28 | Cilag Gmbh International | Method for fabricating surgical stapler anvils |
US11253256B2 (en) | 2018-08-20 | 2022-02-22 | Cilag Gmbh International | Articulatable motor powered surgical instruments with dedicated articulation motor arrangements |
US10912559B2 (en) | 2018-08-20 | 2021-02-09 | Ethicon Llc | Reinforced deformable anvil tip for surgical stapler anvil |
US10856870B2 (en) | 2018-08-20 | 2020-12-08 | Ethicon Llc | Switching arrangements for motor powered articulatable surgical instruments |
EP3846800A4 (en) | 2018-09-04 | 2022-08-24 | C4 Therapeutics, Inc. | Compounds for the degradation of brd9 or mth1 |
JP2022512900A (en) | 2018-11-02 | 2022-02-07 | ダナ-ファーバー キャンサー インスティテュート,インコーポレイテッド | Development and use of acetylation lighter inhibitors |
US20220112201A1 (en) | 2018-11-19 | 2022-04-14 | Dana-Farber Cancer Institute, Inc. | Macrocyclic inhibitors of dyrk1a |
CN113453679A (en) | 2018-12-20 | 2021-09-28 | C4医药公司 | Targeted protein degradation |
EP3935050A4 (en) | 2019-03-06 | 2023-01-04 | C4 Therapeutics, Inc. | Heterocyclic compounds for medical treatment |
WO2020190604A1 (en) | 2019-03-15 | 2020-09-24 | Kura Oncology, Inc. | Methods of treating cancer patients with farnesyltransferase inhibitors |
US11147551B2 (en) | 2019-03-25 | 2021-10-19 | Cilag Gmbh International | Firing drive arrangements for surgical systems |
US11696761B2 (en) | 2019-03-25 | 2023-07-11 | Cilag Gmbh International | Firing drive arrangements for surgical systems |
US11172929B2 (en) | 2019-03-25 | 2021-11-16 | Cilag Gmbh International | Articulation drive arrangements for surgical systems |
US11147553B2 (en) | 2019-03-25 | 2021-10-19 | Cilag Gmbh International | Firing drive arrangements for surgical systems |
US20220153722A1 (en) | 2019-04-04 | 2022-05-19 | Dana-Farber Cancer Institute, Inc. | Cdk2/5 degraders and uses thereof |
SG11202109024YA (en) | 2019-04-12 | 2021-09-29 | C4 Therapeutics Inc | Tricyclic degraders of ikaros and aiolos |
US11903581B2 (en) | 2019-04-30 | 2024-02-20 | Cilag Gmbh International | Methods for stapling tissue using a surgical instrument |
US11432816B2 (en) | 2019-04-30 | 2022-09-06 | Cilag Gmbh International | Articulation pin for a surgical instrument |
US11253254B2 (en) | 2019-04-30 | 2022-02-22 | Cilag Gmbh International | Shaft rotation actuator on a surgical instrument |
US11648009B2 (en) | 2019-04-30 | 2023-05-16 | Cilag Gmbh International | Rotatable jaw tip for a surgical instrument |
US11426251B2 (en) | 2019-04-30 | 2022-08-30 | Cilag Gmbh International | Articulation directional lights on a surgical instrument |
US11471157B2 (en) | 2019-04-30 | 2022-10-18 | Cilag Gmbh International | Articulation control mapping for a surgical instrument |
US11452528B2 (en) | 2019-04-30 | 2022-09-27 | Cilag Gmbh International | Articulation actuators for a surgical instrument |
US20220242882A1 (en) | 2019-05-10 | 2022-08-04 | Dana-Farber Cancer Institute, Inc. | Small-molecule focal adhesion kinase (fak) inhibitors |
US11298127B2 (en) | 2019-06-28 | 2022-04-12 | Cilag GmbH Interational | Surgical stapling system having a lockout mechanism for an incompatible cartridge |
US11298132B2 (en) | 2019-06-28 | 2022-04-12 | Cilag GmbH Inlernational | Staple cartridge including a honeycomb extension |
US11426167B2 (en) | 2019-06-28 | 2022-08-30 | Cilag Gmbh International | Mechanisms for proper anvil attachment surgical stapling head assembly |
US11219455B2 (en) | 2019-06-28 | 2022-01-11 | Cilag Gmbh International | Surgical instrument including a lockout key |
US11684434B2 (en) | 2019-06-28 | 2023-06-27 | Cilag Gmbh International | Surgical RFID assemblies for instrument operational setting control |
US11464601B2 (en) | 2019-06-28 | 2022-10-11 | Cilag Gmbh International | Surgical instrument comprising an RFID system for tracking a movable component |
US11771419B2 (en) | 2019-06-28 | 2023-10-03 | Cilag Gmbh International | Packaging for a replaceable component of a surgical stapling system |
US11259803B2 (en) | 2019-06-28 | 2022-03-01 | Cilag Gmbh International | Surgical stapling system having an information encryption protocol |
US11376098B2 (en) | 2019-06-28 | 2022-07-05 | Cilag Gmbh International | Surgical instrument system comprising an RFID system |
US11399837B2 (en) | 2019-06-28 | 2022-08-02 | Cilag Gmbh International | Mechanisms for motor control adjustments of a motorized surgical instrument |
US11478241B2 (en) | 2019-06-28 | 2022-10-25 | Cilag Gmbh International | Staple cartridge including projections |
US11246678B2 (en) | 2019-06-28 | 2022-02-15 | Cilag Gmbh International | Surgical stapling system having a frangible RFID tag |
US11224497B2 (en) | 2019-06-28 | 2022-01-18 | Cilag Gmbh International | Surgical systems with multiple RFID tags |
US11051807B2 (en) | 2019-06-28 | 2021-07-06 | Cilag Gmbh International | Packaging assembly including a particulate trap |
US11660163B2 (en) | 2019-06-28 | 2023-05-30 | Cilag Gmbh International | Surgical system with RFID tags for updating motor assembly parameters |
US11350938B2 (en) | 2019-06-28 | 2022-06-07 | Cilag Gmbh International | Surgical instrument comprising an aligned rfid sensor |
US11553971B2 (en) | 2019-06-28 | 2023-01-17 | Cilag Gmbh International | Surgical RFID assemblies for display and communication |
US11638587B2 (en) | 2019-06-28 | 2023-05-02 | Cilag Gmbh International | RFID identification systems for surgical instruments |
US11627959B2 (en) | 2019-06-28 | 2023-04-18 | Cilag Gmbh International | Surgical instruments including manual and powered system lockouts |
US11291451B2 (en) | 2019-06-28 | 2022-04-05 | Cilag Gmbh International | Surgical instrument with battery compatibility verification functionality |
US12004740B2 (en) | 2019-06-28 | 2024-06-11 | Cilag Gmbh International | Surgical stapling system having an information decryption protocol |
US11497492B2 (en) | 2019-06-28 | 2022-11-15 | Cilag Gmbh International | Surgical instrument including an articulation lock |
US11523822B2 (en) | 2019-06-28 | 2022-12-13 | Cilag Gmbh International | Battery pack including a circuit interrupter |
KR20220110243A (en) | 2019-12-02 | 2022-08-05 | 셀진 코포레이션 | therapy for the treatment of cancer |
US11234698B2 (en) | 2019-12-19 | 2022-02-01 | Cilag Gmbh International | Stapling system comprising a clamp lockout and a firing lockout |
US11291447B2 (en) | 2019-12-19 | 2022-04-05 | Cilag Gmbh International | Stapling instrument comprising independent jaw closing and staple firing systems |
US11464512B2 (en) | 2019-12-19 | 2022-10-11 | Cilag Gmbh International | Staple cartridge comprising a curved deck surface |
US11529139B2 (en) | 2019-12-19 | 2022-12-20 | Cilag Gmbh International | Motor driven surgical instrument |
US11607219B2 (en) | 2019-12-19 | 2023-03-21 | Cilag Gmbh International | Staple cartridge comprising a detachable tissue cutting knife |
US11701111B2 (en) | 2019-12-19 | 2023-07-18 | Cilag Gmbh International | Method for operating a surgical stapling instrument |
US11446029B2 (en) | 2019-12-19 | 2022-09-20 | Cilag Gmbh International | Staple cartridge comprising projections extending from a curved deck surface |
US11931033B2 (en) | 2019-12-19 | 2024-03-19 | Cilag Gmbh International | Staple cartridge comprising a latch lockout |
US11504122B2 (en) | 2019-12-19 | 2022-11-22 | Cilag Gmbh International | Surgical instrument comprising a nested firing member |
US12035913B2 (en) | 2019-12-19 | 2024-07-16 | Cilag Gmbh International | Staple cartridge comprising a deployable knife |
US11304696B2 (en) | 2019-12-19 | 2022-04-19 | Cilag Gmbh International | Surgical instrument comprising a powered articulation system |
US11529137B2 (en) | 2019-12-19 | 2022-12-20 | Cilag Gmbh International | Staple cartridge comprising driver retention members |
US11559304B2 (en) | 2019-12-19 | 2023-01-24 | Cilag Gmbh International | Surgical instrument comprising a rapid closure mechanism |
US11576672B2 (en) | 2019-12-19 | 2023-02-14 | Cilag Gmbh International | Surgical instrument comprising a closure system including a closure member and an opening member driven by a drive screw |
US11844520B2 (en) | 2019-12-19 | 2023-12-19 | Cilag Gmbh International | Staple cartridge comprising driver retention members |
US11911032B2 (en) | 2019-12-19 | 2024-02-27 | Cilag Gmbh International | Staple cartridge comprising a seating cam |
WO2021141662A1 (en) | 2020-01-10 | 2021-07-15 | Massachusetts Institute Of Technology | Proteolysis targeting chimeric molecules (protacs) with functional handles and uses thereof |
USD975851S1 (en) | 2020-06-02 | 2023-01-17 | Cilag Gmbh International | Staple cartridge |
USD966512S1 (en) | 2020-06-02 | 2022-10-11 | Cilag Gmbh International | Staple cartridge |
USD976401S1 (en) | 2020-06-02 | 2023-01-24 | Cilag Gmbh International | Staple cartridge |
USD967421S1 (en) | 2020-06-02 | 2022-10-18 | Cilag Gmbh International | Staple cartridge |
USD975850S1 (en) | 2020-06-02 | 2023-01-17 | Cilag Gmbh International | Staple cartridge |
USD975278S1 (en) | 2020-06-02 | 2023-01-10 | Cilag Gmbh International | Staple cartridge |
USD974560S1 (en) | 2020-06-02 | 2023-01-03 | Cilag Gmbh International | Staple cartridge |
US20220031320A1 (en) | 2020-07-28 | 2022-02-03 | Cilag Gmbh International | Surgical instruments with flexible firing member actuator constraint arrangements |
US11896217B2 (en) | 2020-10-29 | 2024-02-13 | Cilag Gmbh International | Surgical instrument comprising an articulation lock |
US11452526B2 (en) | 2020-10-29 | 2022-09-27 | Cilag Gmbh International | Surgical instrument comprising a staged voltage regulation start-up system |
US11779330B2 (en) | 2020-10-29 | 2023-10-10 | Cilag Gmbh International | Surgical instrument comprising a jaw alignment system |
US11617577B2 (en) | 2020-10-29 | 2023-04-04 | Cilag Gmbh International | Surgical instrument comprising a sensor configured to sense whether an articulation drive of the surgical instrument is actuatable |
USD980425S1 (en) | 2020-10-29 | 2023-03-07 | Cilag Gmbh International | Surgical instrument assembly |
US11844518B2 (en) | 2020-10-29 | 2023-12-19 | Cilag Gmbh International | Method for operating a surgical instrument |
US11931025B2 (en) | 2020-10-29 | 2024-03-19 | Cilag Gmbh International | Surgical instrument comprising a releasable closure drive lock |
US11517390B2 (en) | 2020-10-29 | 2022-12-06 | Cilag Gmbh International | Surgical instrument comprising a limited travel switch |
US11717289B2 (en) | 2020-10-29 | 2023-08-08 | Cilag Gmbh International | Surgical instrument comprising an indicator which indicates that an articulation drive is actuatable |
US11534259B2 (en) | 2020-10-29 | 2022-12-27 | Cilag Gmbh International | Surgical instrument comprising an articulation indicator |
USD1013170S1 (en) | 2020-10-29 | 2024-01-30 | Cilag Gmbh International | Surgical instrument assembly |
US11627960B2 (en) | 2020-12-02 | 2023-04-18 | Cilag Gmbh International | Powered surgical instruments with smart reload with separately attachable exteriorly mounted wiring connections |
US11744581B2 (en) | 2020-12-02 | 2023-09-05 | Cilag Gmbh International | Powered surgical instruments with multi-phase tissue treatment |
US11653915B2 (en) | 2020-12-02 | 2023-05-23 | Cilag Gmbh International | Surgical instruments with sled location detection and adjustment features |
US11737751B2 (en) | 2020-12-02 | 2023-08-29 | Cilag Gmbh International | Devices and methods of managing energy dissipated within sterile barriers of surgical instrument housings |
US11890010B2 (en) | 2020-12-02 | 2024-02-06 | Cllag GmbH International | Dual-sided reinforced reload for surgical instruments |
US11849943B2 (en) | 2020-12-02 | 2023-12-26 | Cilag Gmbh International | Surgical instrument with cartridge release mechanisms |
US11678882B2 (en) | 2020-12-02 | 2023-06-20 | Cilag Gmbh International | Surgical instruments with interactive features to remedy incidental sled movements |
US11944296B2 (en) | 2020-12-02 | 2024-04-02 | Cilag Gmbh International | Powered surgical instruments with external connectors |
US11653920B2 (en) | 2020-12-02 | 2023-05-23 | Cilag Gmbh International | Powered surgical instruments with communication interfaces through sterile barrier |
US11812964B2 (en) | 2021-02-26 | 2023-11-14 | Cilag Gmbh International | Staple cartridge comprising a power management circuit |
US11701113B2 (en) | 2021-02-26 | 2023-07-18 | Cilag Gmbh International | Stapling instrument comprising a separate power antenna and a data transfer antenna |
US11696757B2 (en) | 2021-02-26 | 2023-07-11 | Cilag Gmbh International | Monitoring of internal systems to detect and track cartridge motion status |
US11980362B2 (en) | 2021-02-26 | 2024-05-14 | Cilag Gmbh International | Surgical instrument system comprising a power transfer coil |
US11744583B2 (en) | 2021-02-26 | 2023-09-05 | Cilag Gmbh International | Distal communication array to tune frequency of RF systems |
US11793514B2 (en) | 2021-02-26 | 2023-10-24 | Cilag Gmbh International | Staple cartridge comprising sensor array which may be embedded in cartridge body |
US11751869B2 (en) | 2021-02-26 | 2023-09-12 | Cilag Gmbh International | Monitoring of multiple sensors over time to detect moving characteristics of tissue |
US11723657B2 (en) | 2021-02-26 | 2023-08-15 | Cilag Gmbh International | Adjustable communication based on available bandwidth and power capacity |
US11950777B2 (en) | 2021-02-26 | 2024-04-09 | Cilag Gmbh International | Staple cartridge comprising an information access control system |
US11730473B2 (en) | 2021-02-26 | 2023-08-22 | Cilag Gmbh International | Monitoring of manufacturing life-cycle |
US11950779B2 (en) | 2021-02-26 | 2024-04-09 | Cilag Gmbh International | Method of powering and communicating with a staple cartridge |
US11749877B2 (en) | 2021-02-26 | 2023-09-05 | Cilag Gmbh International | Stapling instrument comprising a signal antenna |
US11925349B2 (en) | 2021-02-26 | 2024-03-12 | Cilag Gmbh International | Adjustment to transfer parameters to improve available power |
US11737749B2 (en) | 2021-03-22 | 2023-08-29 | Cilag Gmbh International | Surgical stapling instrument comprising a retraction system |
US11723658B2 (en) | 2021-03-22 | 2023-08-15 | Cilag Gmbh International | Staple cartridge comprising a firing lockout |
US11759202B2 (en) | 2021-03-22 | 2023-09-19 | Cilag Gmbh International | Staple cartridge comprising an implantable layer |
US11717291B2 (en) | 2021-03-22 | 2023-08-08 | Cilag Gmbh International | Staple cartridge comprising staples configured to apply different tissue compression |
US11826012B2 (en) | 2021-03-22 | 2023-11-28 | Cilag Gmbh International | Stapling instrument comprising a pulsed motor-driven firing rack |
US11806011B2 (en) | 2021-03-22 | 2023-11-07 | Cilag Gmbh International | Stapling instrument comprising tissue compression systems |
US11826042B2 (en) | 2021-03-22 | 2023-11-28 | Cilag Gmbh International | Surgical instrument comprising a firing drive including a selectable leverage mechanism |
US11849945B2 (en) | 2021-03-24 | 2023-12-26 | Cilag Gmbh International | Rotary-driven surgical stapling assembly comprising eccentrically driven firing member |
US11793516B2 (en) | 2021-03-24 | 2023-10-24 | Cilag Gmbh International | Surgical staple cartridge comprising longitudinal support beam |
US11832816B2 (en) | 2021-03-24 | 2023-12-05 | Cilag Gmbh International | Surgical stapling assembly comprising nonplanar staples and planar staples |
US11786243B2 (en) | 2021-03-24 | 2023-10-17 | Cilag Gmbh International | Firing members having flexible portions for adapting to a load during a surgical firing stroke |
US11896219B2 (en) | 2021-03-24 | 2024-02-13 | Cilag Gmbh International | Mating features between drivers and underside of a cartridge deck |
US11896218B2 (en) | 2021-03-24 | 2024-02-13 | Cilag Gmbh International | Method of using a powered stapling device |
US11857183B2 (en) | 2021-03-24 | 2024-01-02 | Cilag Gmbh International | Stapling assembly components having metal substrates and plastic bodies |
US11849944B2 (en) | 2021-03-24 | 2023-12-26 | Cilag Gmbh International | Drivers for fastener cartridge assemblies having rotary drive screws |
US11786239B2 (en) | 2021-03-24 | 2023-10-17 | Cilag Gmbh International | Surgical instrument articulation joint arrangements comprising multiple moving linkage features |
US11944336B2 (en) | 2021-03-24 | 2024-04-02 | Cilag Gmbh International | Joint arrangements for multi-planar alignment and support of operational drive shafts in articulatable surgical instruments |
US11903582B2 (en) | 2021-03-24 | 2024-02-20 | Cilag Gmbh International | Leveraging surfaces for cartridge installation |
US11744603B2 (en) | 2021-03-24 | 2023-09-05 | Cilag Gmbh International | Multi-axis pivot joints for surgical instruments and methods for manufacturing same |
US11723662B2 (en) | 2021-05-28 | 2023-08-15 | Cilag Gmbh International | Stapling instrument comprising an articulation control display |
US11980363B2 (en) | 2021-10-18 | 2024-05-14 | Cilag Gmbh International | Row-to-row staple array variations |
US11877745B2 (en) | 2021-10-18 | 2024-01-23 | Cilag Gmbh International | Surgical stapling assembly having longitudinally-repeating staple leg clusters |
US11957337B2 (en) | 2021-10-18 | 2024-04-16 | Cilag Gmbh International | Surgical stapling assembly with offset ramped drive surfaces |
US11937816B2 (en) | 2021-10-28 | 2024-03-26 | Cilag Gmbh International | Electrical lead arrangements for surgical instruments |
USD1033637S1 (en) | 2022-01-24 | 2024-07-02 | Forsight Vision4, Inc. | Fluid exchange device |
KR102459196B1 (en) * | 2022-04-08 | 2022-10-27 | 케이블루바이오 주식회사 | A Composition for Preventing or Treating Multiple Myeloma Comprising Novel Chromanone Compounds as Active Ingredients |
WO2023201282A1 (en) | 2022-04-14 | 2023-10-19 | Bristol-Myers Squibb Company | Novel gspt1 compounds and methods of use of the novel compounds |
WO2023220641A2 (en) | 2022-05-11 | 2023-11-16 | Juno Therapeutics, Inc. | Methods and uses related to t cell therapy and production of same |
WO2023220655A1 (en) | 2022-05-11 | 2023-11-16 | Celgene Corporation | Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy |
WO2024097905A1 (en) | 2022-11-02 | 2024-05-10 | Celgene Corporation | Methods of treatment with t cell therapy and immunomodulatory agent maintenance therapy |
WO2024102954A1 (en) | 2022-11-10 | 2024-05-16 | Massachusetts Institute Of Technology | Activation induced clipping system (aics) |
Citations (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3536809A (en) | 1969-02-17 | 1970-10-27 | Alza Corp | Medication method |
US3598123A (en) | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
US3845770A (en) | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US3916899A (en) | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
US4008719A (en) | 1976-02-02 | 1977-02-22 | Alza Corporation | Osmotic system having laminar arrangement for programming delivery of active agent |
US4810643A (en) | 1985-08-23 | 1989-03-07 | Kirin- Amgen Inc. | Production of pluripotent granulocyte colony-stimulating factor |
US4999291A (en) | 1985-08-23 | 1991-03-12 | Amgen Inc. | Production of human pluripotent granulocyte colony-stimulating factor |
US5059595A (en) | 1989-03-22 | 1991-10-22 | Bioresearch, S.P.A. | Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances |
US5073543A (en) | 1988-07-21 | 1991-12-17 | G. D. Searle & Co. | Controlled release formulations of trophic factors in ganglioside-lipsome vehicle |
US5120548A (en) | 1989-11-07 | 1992-06-09 | Merck & Co., Inc. | Swelling modulated polymeric drug delivery device |
US5134127A (en) | 1990-01-23 | 1992-07-28 | University Of Kansas | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
WO1992014455A1 (en) | 1991-02-14 | 1992-09-03 | The Rockefeller University | METHOD FOR CONTROLLING ABNORMAL CONCENTRATION TNF α IN HUMAN TISSUES |
US5229496A (en) | 1985-08-06 | 1993-07-20 | Immunex Corporation | Analogs of human granulocyte-macrophage colony stimulating factor |
WO1994020085A1 (en) | 1993-03-01 | 1994-09-15 | The Children's Medical Center Corporation | Methods and compositions for inhibition of angiogenesis |
US5354556A (en) | 1984-10-30 | 1994-10-11 | Elan Corporation, Plc | Controlled release powder and process for its preparation |
US5528823A (en) | 1992-12-24 | 1996-06-25 | The Whitaker Corporation | Method for retaining wires in a current mode coupler |
US5591767A (en) | 1993-01-25 | 1997-01-07 | Pharmetrix Corporation | Liquid reservoir transdermal patch for the administration of ketorolac |
US5635517A (en) | 1996-07-24 | 1997-06-03 | Celgene Corporation | Method of reducing TNFα levels with amino substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxo-and 1,3-dioxoisoindolines |
US5639476A (en) | 1992-01-27 | 1997-06-17 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
US5674533A (en) | 1994-07-07 | 1997-10-07 | Recordati, S.A., Chemical And Pharmaceutical Company | Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension |
US5698579A (en) | 1993-07-02 | 1997-12-16 | Celgene Corporation | Cyclic amides |
WO1998003502A1 (en) | 1996-07-24 | 1998-01-29 | Celgene Corporation | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels |
US5731325A (en) | 1995-06-06 | 1998-03-24 | Andrulis Pharmaceuticals Corp. | Treatment of melanomas with thalidomide alone or in combination with other anti-melanoma agents |
US5733566A (en) | 1990-05-15 | 1998-03-31 | Alkermes Controlled Therapeutics Inc. Ii | Controlled release of antiparasitic agents in animals |
US5798368A (en) | 1996-08-22 | 1998-08-25 | Celgene Corporation | Tetrasubstituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines and method of reducing TNFα levels |
WO1998054170A1 (en) | 1997-05-30 | 1998-12-03 | Celgene Corporation | SUBSTITUTED 2-(2,6-DIOXOPIPERIDIN-3-YL)-PHTHALIMIDES AND 1-OXOISOINDOLINES AND METHOD OF REDUCING TNFα LEVELS |
US5874448A (en) | 1997-11-18 | 1999-02-23 | Celgene Corporation | Substituted 2-(2,6 dioxo-3-fluoropiperidin-3-yl)-isoindolines and method of reducing TNFα levels |
US5929117A (en) | 1996-08-12 | 1999-07-27 | Celgene Corporation | Immunotherapeutic agents |
US5955476A (en) | 1997-11-18 | 1999-09-21 | Celgene Corporation | Substituted 2-(2,6-dioxo-3-fluoropiperidin-3-yl)-isoindolines and method of reducing inflammatory cytokine levels |
US6020358A (en) | 1998-10-30 | 2000-02-01 | Celgene Corporation | Substituted phenethylsulfones and method of reducing TNFα levels |
US6077822A (en) * | 1993-09-14 | 2000-06-20 | Dumex-Alpharma A/S | Drug salts |
US6114355A (en) | 1993-03-01 | 2000-09-05 | D'amato; Robert | Methods and compositions for inhibition of angiogenesis |
US6228879B1 (en) | 1997-10-16 | 2001-05-08 | The Children's Medical Center | Methods and compositions for inhibition of angiogenesis |
US6281230B1 (en) | 1996-07-24 | 2001-08-28 | Celgene Corporation | Isoindolines, method of use, and pharmaceutical compositions |
US20010018445A1 (en) | 2000-02-02 | 2001-08-30 | Tty Biopharm Company Limited | Pharmaceutical composition for the treatment of hepatocellular carcinoma |
WO2001070275A2 (en) | 2000-03-17 | 2001-09-27 | Cell Therapeutics, Inc. | Polyglutamic acid-camptothecin conjugates and methods of preparation |
WO2001087307A2 (en) | 2000-05-15 | 2001-11-22 | Celgene Corp. | Compositions and methods for the treatment of cancer |
US6326388B1 (en) | 1999-12-21 | 2001-12-04 | Celgene Corporation | Substituted 1,3,4-oxadiazoles and a method of reducing TNF-alpha level |
US20010056114A1 (en) | 2000-11-01 | 2001-12-27 | D'amato Robert | Methods for the inhibition of angiogenesis with 3-amino thalidomide |
WO2002015926A1 (en) | 2000-08-24 | 2002-02-28 | Kirin Beer Kabushiki Kaisha | c-mpl LIGAND-CONTAINING MEDICINAL COMPOSITIONS FOR INCREASING PLATELETS AND ERYTHROCYTES |
US6380239B1 (en) | 1999-03-18 | 2002-04-30 | Celgene Corporation | Substituted 1-oxo- and 1,3-dioxoisoindoline and method of reducing inflammatory cytokine levels |
US20020054899A1 (en) | 1999-12-15 | 2002-05-09 | Zeldis Jerome B. | Methods and compositions for the prevention and treatment of atherosclerosis, restenosis and related disorders |
US6403613B1 (en) | 1998-03-16 | 2002-06-11 | Hon-Wah Man | 1-oxo-and 1,3-dioxoisoindolines |
WO2002059106A1 (en) | 2000-12-27 | 2002-08-01 | Celgene Corporation | Isoindole-imide compounds, compositions, and uses thereof |
WO2002064083A2 (en) | 2000-11-30 | 2002-08-22 | The Children's Medical Center Corporation | Synthesis of 3-amino-thalidomide and its enantiomers |
US20020128228A1 (en) | 2000-12-01 | 2002-09-12 | Wen-Jen Hwu | Compositions and methods for the treatment of cancer |
US6458810B1 (en) | 2000-11-14 | 2002-10-01 | George Muller | Pharmaceutically active isoindoline derivatives |
US20030013739A1 (en) | 1998-12-23 | 2003-01-16 | Pharmacia Corporation | Methods of using a combination of cyclooxygenase-2 selective inhibitors and thalidomide for the treatment of neoplasia |
US20030096841A1 (en) | 2000-12-27 | 2003-05-22 | Robarge Michael J. | Isoindole-imide compounds, compositions, and uses thereof |
US20030139451A1 (en) | 2001-08-06 | 2003-07-24 | Shah Jamshed H. | Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs |
US20030191098A1 (en) | 1996-11-05 | 2003-10-09 | D'amato Robert J. | Methods and compositions for inhibition of angiogenesis |
WO2003086373A1 (en) | 2002-04-12 | 2003-10-23 | Celgene Corporation | Methods for identification of modulators of angiogenesis, compounds discovered thereby, and methods of treatment using the compounds |
US20030235909A1 (en) | 2002-04-12 | 2003-12-25 | Hariri Robert J. | Modulation of stem and progenitor cell differentiation, assays, and uses thereof |
US6673828B1 (en) | 1998-05-11 | 2004-01-06 | Children's Medical Center Corporation | Analogs of 2-Phthalimidinoglutaric acid |
US20040029832A1 (en) | 2002-05-17 | 2004-02-12 | Zeldis Jerome B. | Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases |
US20040077686A1 (en) | 2000-03-31 | 2004-04-22 | Dannenberg Andrew J. | Inhibition of cyclooxygenase-2 activity |
US20040077685A1 (en) | 2001-02-27 | 2004-04-22 | Figg William D. | Analogs of thalidomide as potential angiogenesis inhibitors |
US20040087546A1 (en) | 2002-11-06 | 2004-05-06 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of myeloproliferative diseases |
US20040091455A1 (en) | 2002-10-31 | 2004-05-13 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for treatment and management of macular degeneration |
US20040266809A1 (en) | 2003-05-19 | 2004-12-30 | David Emanuel | Method of treating multiple myeloma |
US7393862B2 (en) | 2002-05-17 | 2008-07-01 | Celgene Corporation | Method using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for treatment of certain leukemias |
Family Cites Families (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4551177A (en) * | 1984-04-23 | 1985-11-05 | National Starch And Chemical Corporation | Compressible starches as binders for tablets or capsules |
US5059959A (en) * | 1985-06-03 | 1991-10-22 | Seven Oaks Corporation | Cursor positioning method and apparatus |
US5974203A (en) | 1988-04-11 | 1999-10-26 | Canon Kabushiki Kaisha | Pattern recognition communication apparatus for transmitting and receiving image data |
US5387421A (en) * | 1991-01-31 | 1995-02-07 | Tsrl, Inc. | Multi stage drug delivery system |
US5164295A (en) * | 1991-03-06 | 1992-11-17 | The Upjohn Company | Method for identifying amyloid protein-extracellular matrix protein affinity altering compounds |
US5358941A (en) | 1992-12-02 | 1994-10-25 | Merck & Co., Inc. | Dry mix formulation for bisphosphonic acids with lactose |
US5594637A (en) | 1993-05-26 | 1997-01-14 | Base Ten Systems, Inc. | System and method for assessing medical risk |
US5712191A (en) * | 1994-09-16 | 1998-01-27 | Semiconductor Energy Laboratory Co., Ltd. | Method for producing semiconductor device |
BR9509357A (en) | 1994-10-28 | 1997-12-30 | Advanced Health Med E Systems | Prescription management system implemented in a computer prescription combination formed by a central computer installation in a prescription management system packaging, dosage indication device and product specification system for professional use |
US5593696A (en) | 1994-11-21 | 1997-01-14 | Mcneil-Ppc, Inc. | Stabilized composition of famotidine and sucralfate for treatment of gastrointestinal disorders |
WO1996026726A1 (en) * | 1995-02-28 | 1996-09-06 | Hoechst Marion Roussel, Inc. | Pharmaceutical composition for piperidinoalkanol compounds |
US5619991A (en) | 1995-04-26 | 1997-04-15 | Lucent Technologies Inc. | Delivery of medical services using electronic data communications |
US5832449A (en) | 1995-11-13 | 1998-11-03 | Cunningham; David W. | Method and system for dispensing, tracking and managing pharmaceutical trial products |
US6063026A (en) | 1995-12-07 | 2000-05-16 | Carbon Based Corporation | Medical diagnostic analysis system |
US5924074A (en) | 1996-09-27 | 1999-07-13 | Azron Incorporated | Electronic medical records system |
US6131090A (en) | 1997-03-04 | 2000-10-10 | Pitney Bowes Inc. | Method and system for providing controlled access to information stored on a portable recording medium |
GB9705035D0 (en) * | 1997-03-11 | 1997-04-30 | Pharmacia & Upjohn Spa | Indolyl-pyrrolydenemethylpyrrole derivatives and process for their preparation |
AU8909898A (en) | 1997-08-22 | 1999-03-16 | Deka Products Limited Partnership | Health care system and method for physician order entry |
TR200003800T2 (en) * | 1998-06-22 | 2001-06-21 | American Biogenetic Sciences, Inc. | The use of valproic acid analogues in the treatment and prevention of migraine |
US6045501A (en) | 1998-08-28 | 2000-04-04 | Celgene Corporation | Methods for delivering a drug to a patient while preventing the exposure of a foetus or other contraindicated individual to the drug |
CA2333626A1 (en) * | 1998-12-18 | 2000-06-29 | Angiosonics Inc. | Method for prevention and treatment of cancer and other cell proliferative diseases with ultrasonics |
GB9904585D0 (en) | 1999-02-26 | 1999-04-21 | Gemini Research Limited | Clinical and diagnostic database |
US7244450B2 (en) | 1999-04-01 | 2007-07-17 | Inex Pharmaceuticals Corporation | Compositions and methods for treating lymphoma |
US7629360B2 (en) | 1999-05-07 | 2009-12-08 | Celgene Corporation | Methods for the treatment of cachexia and graft v. host disease |
US6202923B1 (en) | 1999-08-23 | 2001-03-20 | Innovation Associates, Inc. | Automated pharmacy |
US6878733B1 (en) | 1999-11-24 | 2005-04-12 | Sugen, Inc. | Formulations for pharmaceutical agents ionizable as free acids or free bases |
UA74539C2 (en) * | 1999-12-08 | 2006-01-16 | Pharmacia Corp | Crystalline polymorphous forms of celecoxib (variants), a method for the preparation thereof (variants), a pharmaceutical composition (variants) |
SI1296714T1 (en) * | 2000-06-22 | 2010-01-29 | S For Entpr University Of Iowa | Combination of CpG and antibodies directed against CD19,CD20, CD22 or CD40 for the treatment or prevention of cancer. |
WO2002027019A1 (en) * | 2000-09-29 | 2002-04-04 | The Johns Hopkins University School Of Medicine | Method of predicting the clinical response to chemotherapeutic treatment with alkylating agents |
ES2186484B1 (en) * | 2000-10-10 | 2004-07-01 | Lipotec, S.A. | LIPOSOMES ENCAPSULATING ANTI-CANCER DRUGS AND USE OF THEM IN THE TREATMENT OF EVIL TUMORS. |
US6315720B1 (en) | 2000-10-23 | 2001-11-13 | Celgene Corporation | Methods for delivering a drug to a patient while avoiding the occurrence of an adverse side effect known or suspected of being caused by the drug |
US20030065000A1 (en) * | 2001-09-07 | 2003-04-03 | Cohen Pamela Sarah | Method of treating cancer |
EP1443927B1 (en) * | 2001-11-07 | 2007-01-10 | Millennium Pharmaceuticals, Inc. | Carboline derivatives as inhibitors of ikb in the treatment of multiple myeloma |
US6797708B2 (en) * | 2001-12-03 | 2004-09-28 | Wyeth | Inhibitors of cytosolic phospholipase A2 |
TWI323658B (en) * | 2001-12-06 | 2010-04-21 | Nat Health Research Institutes | Novel compounds of indol-3-yl-2-oxyacetylamide derivatives, pharmaceutical composition thereof, and method for manufacturing the same |
NZ535349A (en) * | 2002-03-08 | 2007-01-26 | Signal Pharm Inc | JNK inhibitors with chemotherapeutic agents in a combination therapy for treating or preventing cancer and other proliferative disorders in refractory patients in particular |
JP4027693B2 (en) | 2002-03-20 | 2007-12-26 | トリニティ工業株式会社 | Paint feeding device and valve unit |
US7323479B2 (en) | 2002-05-17 | 2008-01-29 | Celgene Corporation | Methods for treatment and management of brain cancer using 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-methylisoindoline |
US7189740B2 (en) * | 2002-10-15 | 2007-03-13 | Celgene Corporation | Methods of using 3-(4-amino-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for the treatment and management of myelodysplastic syndromes |
UA83504C2 (en) | 2003-09-04 | 2008-07-25 | Селджин Корпорейшн | Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione |
US20070155791A1 (en) | 2005-12-29 | 2007-07-05 | Zeldis Jerome B | Methods for treating cutaneous lupus using aminoisoindoline compounds |
ES2728776T3 (en) | 2009-05-19 | 2019-10-28 | Celgene Corp | 4-amino-2- (2,6-dioxopiperidin-3-yl) isoindolin-1,3-dione formulations |
-
2003
- 2003-05-15 US US10/438,213 patent/US7968569B2/en not_active Expired - Lifetime
- 2003-11-06 JP JP2005507108A patent/JP4754967B2/en not_active Expired - Lifetime
- 2003-11-06 TW TW098132747A patent/TWI492746B/en active
- 2003-11-06 CA CA002505128A patent/CA2505128C/en not_active Expired - Fee Related
- 2003-11-06 TW TW095140336A patent/TWI430793B/en not_active IP Right Cessation
- 2003-11-06 TW TW101130538A patent/TWI492748B/en active
- 2003-11-06 EP EP03783233A patent/EP1567158A4/en not_active Withdrawn
- 2003-11-06 MX MXPA05004734A patent/MXPA05004734A/en active IP Right Grant
- 2003-11-06 KR KR1020057008120A patent/KR101131651B1/en not_active IP Right Cessation
- 2003-11-06 AU AU2003290651A patent/AU2003290651B2/en not_active Ceased
- 2003-11-06 WO PCT/US2003/035544 patent/WO2004043377A2/en active Application Filing
- 2003-11-06 TW TW092131080A patent/TWI308913B/en not_active IP Right Cessation
- 2003-11-06 NZ NZ540385A patent/NZ540385A/en not_active IP Right Cessation
- 2003-11-06 BR BR0316050-5A patent/BR0316050A/en not_active Application Discontinuation
-
2005
- 2005-04-08 US US11/102,742 patent/US7468363B2/en not_active Expired - Lifetime
- 2005-11-04 US US11/267,896 patent/US20060069065A1/en not_active Abandoned
-
2006
- 2006-01-04 US US11/325,954 patent/US20060105993A1/en not_active Abandoned
- 2006-03-07 US US11/370,560 patent/US20060172970A1/en not_active Abandoned
-
2007
- 2007-07-27 US US11/881,756 patent/US20070299020A1/en not_active Abandoned
-
2008
- 2008-04-22 US US12/148,796 patent/US20090010877A1/en not_active Abandoned
- 2008-04-25 US US12/150,341 patent/US20080206193A1/en not_active Abandoned
- 2008-05-08 US US12/151,757 patent/US20080219948A1/en not_active Abandoned
- 2008-05-08 US US12/151,759 patent/US20080286232A1/en not_active Abandoned
- 2008-05-08 US US12/151,758 patent/US8207200B2/en not_active Expired - Lifetime
- 2008-05-08 US US12/151,760 patent/US20080219949A1/en not_active Abandoned
- 2008-08-19 US US12/229,074 patent/US8198262B2/en active Active
- 2008-08-19 US US12/229,075 patent/US20080317709A1/en not_active Abandoned
-
2009
- 2009-01-15 US US12/354,249 patent/US20090123416A1/en not_active Abandoned
- 2009-02-19 US US12/388,886 patent/US8188118B2/en not_active Expired - Fee Related
- 2009-11-18 US US12/621,038 patent/US20100063094A1/en not_active Abandoned
- 2009-12-17 US US12/640,702 patent/US8198306B2/en not_active Expired - Fee Related
- 2009-12-17 US US12/641,245 patent/US20100099711A1/en not_active Abandoned
-
2010
- 2010-04-07 US US12/755,875 patent/US8492406B2/en active Active
- 2010-04-07 US US12/755,904 patent/US8410136B2/en not_active Expired - Lifetime
-
2011
- 2011-10-19 US US13/276,867 patent/US20120035145A1/en not_active Abandoned
-
2012
- 2012-05-30 US US13/483,832 patent/US8722647B2/en not_active Expired - Lifetime
- 2012-06-05 US US13/488,888 patent/US8648095B2/en not_active Expired - Lifetime
-
2013
- 2013-01-14 US US13/740,969 patent/US8759375B2/en not_active Expired - Lifetime
- 2013-03-01 US US13/782,612 patent/US8735428B2/en not_active Expired - Lifetime
- 2013-03-01 US US13/782,728 patent/US8673939B2/en not_active Expired - Lifetime
- 2013-04-08 US US13/858,708 patent/US8530498B1/en not_active Expired - Lifetime
- 2013-07-15 US US13/942,232 patent/US8722705B2/en not_active Expired - Lifetime
-
2014
- 2014-03-07 US US14/201,069 patent/US9283215B2/en not_active Expired - Fee Related
- 2014-03-25 US US14/224,974 patent/US9050324B2/en not_active Expired - Lifetime
- 2014-03-26 US US14/225,970 patent/US9155730B2/en not_active Expired - Lifetime
- 2014-04-17 US US14/255,211 patent/US9101621B2/en not_active Expired - Lifetime
- 2014-09-10 US US14/482,745 patent/US9101622B2/en not_active Expired - Lifetime
- 2014-12-08 US US14/563,613 patent/US9393238B2/en not_active Expired - Lifetime
- 2014-12-09 US US14/564,693 patent/US20150094336A1/en not_active Abandoned
-
2015
- 2015-03-19 US US14/662,788 patent/US20150190386A1/en not_active Abandoned
- 2015-09-24 US US14/864,121 patent/US20160008345A1/en not_active Abandoned
-
2016
- 2016-05-20 US US15/161,048 patent/US9662321B2/en not_active Expired - Lifetime
-
2017
- 2017-01-03 US US15/397,643 patent/US10206914B2/en not_active Ceased
-
2019
- 2019-02-15 US US16/277,936 patent/US20190175575A1/en not_active Abandoned
Patent Citations (96)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3536809A (en) | 1969-02-17 | 1970-10-27 | Alza Corp | Medication method |
US3598123A (en) | 1969-04-01 | 1971-08-10 | Alza Corp | Bandage for administering drugs |
US3845770A (en) | 1972-06-05 | 1974-11-05 | Alza Corp | Osmatic dispensing device for releasing beneficial agent |
US3916899A (en) | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
US4008719A (en) | 1976-02-02 | 1977-02-22 | Alza Corporation | Osmotic system having laminar arrangement for programming delivery of active agent |
US5354556A (en) | 1984-10-30 | 1994-10-11 | Elan Corporation, Plc | Controlled release powder and process for its preparation |
US5229496A (en) | 1985-08-06 | 1993-07-20 | Immunex Corporation | Analogs of human granulocyte-macrophage colony stimulating factor |
US5391485A (en) | 1985-08-06 | 1995-02-21 | Immunex Corporation | DNAs encoding analog GM-CSF molecules displaying resistance to proteases which cleave at adjacent dibasic residues |
US5393870A (en) | 1985-08-06 | 1995-02-28 | Immunex Corporation | Analogs of human granulocyte-macrophage colony stimulating factor |
US4999291A (en) | 1985-08-23 | 1991-03-12 | Amgen Inc. | Production of human pluripotent granulocyte colony-stimulating factor |
US5580755A (en) | 1985-08-23 | 1996-12-03 | Amgen Inc. | Human pluripotent granulocyte colony-stimulating factor |
US4810643A (en) | 1985-08-23 | 1989-03-07 | Kirin- Amgen Inc. | Production of pluripotent granulocyte colony-stimulating factor |
US5073543A (en) | 1988-07-21 | 1991-12-17 | G. D. Searle & Co. | Controlled release formulations of trophic factors in ganglioside-lipsome vehicle |
US5059595A (en) | 1989-03-22 | 1991-10-22 | Bioresearch, S.P.A. | Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances |
US5120548A (en) | 1989-11-07 | 1992-06-09 | Merck & Co., Inc. | Swelling modulated polymeric drug delivery device |
US5134127A (en) | 1990-01-23 | 1992-07-28 | University Of Kansas | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
US5733566A (en) | 1990-05-15 | 1998-03-31 | Alkermes Controlled Therapeutics Inc. Ii | Controlled release of antiparasitic agents in animals |
US5385901A (en) | 1991-02-14 | 1995-01-31 | The Rockefeller University | Method of treating abnormal concentrations of TNF α |
WO1992014455A1 (en) | 1991-02-14 | 1992-09-03 | The Rockefeller University | METHOD FOR CONTROLLING ABNORMAL CONCENTRATION TNF α IN HUMAN TISSUES |
US5639476A (en) | 1992-01-27 | 1997-06-17 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
US5528823A (en) | 1992-12-24 | 1996-06-25 | The Whitaker Corporation | Method for retaining wires in a current mode coupler |
US5591767A (en) | 1993-01-25 | 1997-01-07 | Pharmetrix Corporation | Liquid reservoir transdermal patch for the administration of ketorolac |
US6469045B1 (en) | 1993-03-01 | 2002-10-22 | The Children's Medical Center Corporation | Methods and compositions for inhibition of angiogenesis with EM-138 |
US20020061923A1 (en) | 1993-03-01 | 2002-05-23 | D'amato Robert | Methods and compositions for inhibition of angiogenesis with EM-138 |
US5629327A (en) | 1993-03-01 | 1997-05-13 | Childrens Hospital Medical Center Corp. | Methods and compositions for inhibition of angiogenesis |
US6071948A (en) | 1993-03-01 | 2000-06-06 | The Children's Medical Center Corporation | Methods and compositions for inhibition of angiogenesis |
US6235756B1 (en) | 1993-03-01 | 2001-05-22 | The Children's Medical Center Corporation | Methods and compositions for inhibition of angiogenesis by thalidomide |
US5712291A (en) | 1993-03-01 | 1998-01-27 | The Children's Medical Center Corporation | Methods and compositions for inhibition of angiogenesis |
US6420414B1 (en) | 1993-03-01 | 2002-07-16 | The Children's Medical Center Corporation | Amino derivatives of EM-138 and methods of treating angiogenesis with same |
US20030187024A1 (en) | 1993-03-01 | 2003-10-02 | D'amato Robert | Methods and compositions for inhibition of angiogenesis |
US6114355A (en) | 1993-03-01 | 2000-09-05 | D'amato; Robert | Methods and compositions for inhibition of angiogenesis |
US20020161023A1 (en) | 1993-03-01 | 2002-10-31 | D'amato Robert | Method of treating diseases using 3-amino thalidomide |
US20020052398A1 (en) | 1993-03-01 | 2002-05-02 | D'amato Robert J. | Pharmaceutical composition of 6-amino EM-12 |
US5593990A (en) | 1993-03-01 | 1997-01-14 | The Children's Medical Center Corporation | Methods and compositions for inhibition of angiogenesis |
WO1994020085A1 (en) | 1993-03-01 | 1994-09-15 | The Children's Medical Center Corporation | Methods and compositions for inhibition of angiogenesis |
US5877200A (en) | 1993-07-02 | 1999-03-02 | Celgene Corporation | Cyclic amides |
US5698579A (en) | 1993-07-02 | 1997-12-16 | Celgene Corporation | Cyclic amides |
US6077822A (en) * | 1993-09-14 | 2000-06-20 | Dumex-Alpharma A/S | Drug salts |
US5674533A (en) | 1994-07-07 | 1997-10-07 | Recordati, S.A., Chemical And Pharmaceutical Company | Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension |
US5731325A (en) | 1995-06-06 | 1998-03-24 | Andrulis Pharmaceuticals Corp. | Treatment of melanomas with thalidomide alone or in combination with other anti-melanoma agents |
US6140346A (en) | 1995-06-06 | 2000-10-31 | Andrulis Pharmaceuticals Corp. | Treatment of cancer with thalidomide alone or in combination with other anti-cancer agents |
US6316471B1 (en) | 1996-07-24 | 2001-11-13 | Celgene Corporation | Isoindolines, method of use, and pharmaceutical compositions |
US6335349B1 (en) | 1996-07-24 | 2002-01-01 | Celgene Corporation | Substituted 2(2,6-dioxopiperidin-3-yl)isoindolines |
US5635517A (en) | 1996-07-24 | 1997-06-03 | Celgene Corporation | Method of reducing TNFα levels with amino substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxo-and 1,3-dioxoisoindolines |
WO1998003502A1 (en) | 1996-07-24 | 1998-01-29 | Celgene Corporation | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and method of reducing tnf-alpha levels |
US6281230B1 (en) | 1996-07-24 | 2001-08-28 | Celgene Corporation | Isoindolines, method of use, and pharmaceutical compositions |
US6476052B1 (en) | 1996-07-24 | 2002-11-05 | Celgene Corporation | Isoindolines, method of use, and pharmaceutical compositions |
US20020183360A1 (en) | 1996-07-24 | 2002-12-05 | Muller George W. | Substituted 2-(2,6-dioxopiperidin-3-YL)-phthalimides and -1-oxoisoindolines and method of reducing TNFalpha levels |
US5635517B1 (en) | 1996-07-24 | 1999-06-29 | Celgene Corp | Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines |
US20020045643A1 (en) | 1996-07-24 | 2002-04-18 | Muller George W. | Isoindolines, method of use, and pharmaceutical compositions |
US20030144325A1 (en) | 1996-07-24 | 2003-07-31 | Muller George W. | Isoindolines, method of use, and pharmaceutical compositions |
US6555554B2 (en) | 1996-07-24 | 2003-04-29 | Celgene Corporation | Isoindolines, method of use, and pharmaceutical compositions |
US5929117A (en) | 1996-08-12 | 1999-07-27 | Celgene Corporation | Immunotherapeutic agents |
US5798368A (en) | 1996-08-22 | 1998-08-25 | Celgene Corporation | Tetrasubstituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines and method of reducing TNFα levels |
US7435745B2 (en) | 1996-11-05 | 2008-10-14 | Celgene Corporation | Methods and compositions for inhibition of angiogenesis |
US20030191098A1 (en) | 1996-11-05 | 2003-10-09 | D'amato Robert J. | Methods and compositions for inhibition of angiogenesis |
WO1998054170A1 (en) | 1997-05-30 | 1998-12-03 | Celgene Corporation | SUBSTITUTED 2-(2,6-DIOXOPIPERIDIN-3-YL)-PHTHALIMIDES AND 1-OXOISOINDOLINES AND METHOD OF REDUCING TNFα LEVELS |
US20020173658A1 (en) | 1997-05-30 | 2002-11-21 | Muller George W. | Substituted 2-(2,6-dioxopiperidin-3-yl)-phthalimides and-1-oxoisoindolines and method of reducing TNFalpha levels |
US6395754B1 (en) | 1997-05-30 | 2002-05-28 | Celgene Corporation, Et Al. | Substituted 2-(2,6-dioxopiperidin-3-yl)- phthalimides and 1-oxoisoindolines and method of reducing TNFα levels |
US6518298B2 (en) | 1997-10-16 | 2003-02-11 | Entremed, Inc. | Methods and compositions for inhibition of angiogenesis with EM-138 |
US20030181428A1 (en) | 1997-10-16 | 2003-09-25 | Green Shawn J. | Methods and compositions for inhibition of angiogenesis |
US6228879B1 (en) | 1997-10-16 | 2001-05-08 | The Children's Medical Center | Methods and compositions for inhibition of angiogenesis |
US5874448A (en) | 1997-11-18 | 1999-02-23 | Celgene Corporation | Substituted 2-(2,6 dioxo-3-fluoropiperidin-3-yl)-isoindolines and method of reducing TNFα levels |
US5955476A (en) | 1997-11-18 | 1999-09-21 | Celgene Corporation | Substituted 2-(2,6-dioxo-3-fluoropiperidin-3-yl)-isoindolines and method of reducing inflammatory cytokine levels |
US20030028028A1 (en) | 1998-03-16 | 2003-02-06 | Hon-Wah Man | 1-oxo- and 1,3-dioxoisoindolines and method of reducing inflammatory cytokine levels |
US6403613B1 (en) | 1998-03-16 | 2002-06-11 | Hon-Wah Man | 1-oxo-and 1,3-dioxoisoindolines |
US6673828B1 (en) | 1998-05-11 | 2004-01-06 | Children's Medical Center Corporation | Analogs of 2-Phthalimidinoglutaric acid |
US6020358A (en) | 1998-10-30 | 2000-02-01 | Celgene Corporation | Substituted phenethylsulfones and method of reducing TNFα levels |
US20030013739A1 (en) | 1998-12-23 | 2003-01-16 | Pharmacia Corporation | Methods of using a combination of cyclooxygenase-2 selective inhibitors and thalidomide for the treatment of neoplasia |
US6380239B1 (en) | 1999-03-18 | 2002-04-30 | Celgene Corporation | Substituted 1-oxo- and 1,3-dioxoisoindoline and method of reducing inflammatory cytokine levels |
US20020054899A1 (en) | 1999-12-15 | 2002-05-09 | Zeldis Jerome B. | Methods and compositions for the prevention and treatment of atherosclerosis, restenosis and related disorders |
US6326388B1 (en) | 1999-12-21 | 2001-12-04 | Celgene Corporation | Substituted 1,3,4-oxadiazoles and a method of reducing TNF-alpha level |
US20010018445A1 (en) | 2000-02-02 | 2001-08-30 | Tty Biopharm Company Limited | Pharmaceutical composition for the treatment of hepatocellular carcinoma |
WO2001070275A2 (en) | 2000-03-17 | 2001-09-27 | Cell Therapeutics, Inc. | Polyglutamic acid-camptothecin conjugates and methods of preparation |
US20040077686A1 (en) | 2000-03-31 | 2004-04-22 | Dannenberg Andrew J. | Inhibition of cyclooxygenase-2 activity |
US20020035090A1 (en) | 2000-05-15 | 2002-03-21 | Zeldis Jerome B. | Compositions and methods for the treatment of cancer |
WO2001087307A2 (en) | 2000-05-15 | 2001-11-22 | Celgene Corp. | Compositions and methods for the treatment of cancer |
WO2002015926A1 (en) | 2000-08-24 | 2002-02-28 | Kirin Beer Kabushiki Kaisha | c-mpl LIGAND-CONTAINING MEDICINAL COMPOSITIONS FOR INCREASING PLATELETS AND ERYTHROCYTES |
US20010056114A1 (en) | 2000-11-01 | 2001-12-27 | D'amato Robert | Methods for the inhibition of angiogenesis with 3-amino thalidomide |
US20040122052A1 (en) | 2000-11-14 | 2004-06-24 | Celgene Corporation | Pharmaceutically active isoindoline derivatives |
US20030069428A1 (en) | 2000-11-14 | 2003-04-10 | George Muller | Pharmaceutically active isoindoline derivatives |
US6458810B1 (en) | 2000-11-14 | 2002-10-01 | George Muller | Pharmaceutically active isoindoline derivatives |
WO2002064083A2 (en) | 2000-11-30 | 2002-08-22 | The Children's Medical Center Corporation | Synthesis of 3-amino-thalidomide and its enantiomers |
US20020128228A1 (en) | 2000-12-01 | 2002-09-12 | Wen-Jen Hwu | Compositions and methods for the treatment of cancer |
US20030045552A1 (en) | 2000-12-27 | 2003-03-06 | Robarge Michael J. | Isoindole-imide compounds, compositions, and uses thereof |
US20030096841A1 (en) | 2000-12-27 | 2003-05-22 | Robarge Michael J. | Isoindole-imide compounds, compositions, and uses thereof |
WO2002059106A1 (en) | 2000-12-27 | 2002-08-01 | Celgene Corporation | Isoindole-imide compounds, compositions, and uses thereof |
US20040077685A1 (en) | 2001-02-27 | 2004-04-22 | Figg William D. | Analogs of thalidomide as potential angiogenesis inhibitors |
US20030139451A1 (en) | 2001-08-06 | 2003-07-24 | Shah Jamshed H. | Synthesis and anti-tumor activity of nitrogen substituted thalidomide analogs |
US20030235909A1 (en) | 2002-04-12 | 2003-12-25 | Hariri Robert J. | Modulation of stem and progenitor cell differentiation, assays, and uses thereof |
WO2003086373A1 (en) | 2002-04-12 | 2003-10-23 | Celgene Corporation | Methods for identification of modulators of angiogenesis, compounds discovered thereby, and methods of treatment using the compounds |
US20040029832A1 (en) | 2002-05-17 | 2004-02-12 | Zeldis Jerome B. | Methods and compositions using immunomodulatory compounds for treatment and management of cancers and other diseases |
US7393862B2 (en) | 2002-05-17 | 2008-07-01 | Celgene Corporation | Method using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for treatment of certain leukemias |
US20040091455A1 (en) | 2002-10-31 | 2004-05-13 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for treatment and management of macular degeneration |
US20040087546A1 (en) | 2002-11-06 | 2004-05-06 | Zeldis Jerome B. | Methods of using and compositions comprising immunomodulatory compounds for the treatment and management of myeloproliferative diseases |
US20040266809A1 (en) | 2003-05-19 | 2004-12-30 | David Emanuel | Method of treating multiple myeloma |
Non-Patent Citations (279)
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9101622B2 (en) | 2002-05-17 | 2015-08-11 | Celgene Corporation | Methods for treating newly diagnosed multiple myeloma 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in combination with dexamethasone |
US9393238B2 (en) | 2002-05-17 | 2016-07-19 | Celgene Corporation | Methods for treating non-hodgkin's lymphoma with 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in combination with a second active agent |
US9498472B2 (en) | 2002-05-17 | 2016-11-22 | Celgene Corporation | Methods using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for treatment of certain leukemias |
US9662321B2 (en) | 2002-05-17 | 2017-05-30 | Celgene Corporation | Methods for treating newly diagnosed multiple myeloma with 3-(4-amino-1-OXO-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione in combination with second active agents |
US10206914B2 (en) | 2002-05-17 | 2019-02-19 | Celgene Corporation | Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation |
USRE48890E1 (en) | 2002-05-17 | 2022-01-11 | Celgene Corporation | Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation |
US9226913B2 (en) | 2010-01-05 | 2016-01-05 | Celgene Corporation | Methods of treating cancer using a combination of an immunomodulatory compound and an artemisinin or a derivative thereof |
US10034872B2 (en) | 2014-08-22 | 2018-07-31 | Celgene Corporation | Methods of treating multiple myeloma with immunomodulatory compounds in combination with antibodies |
US11266599B2 (en) | 2018-02-07 | 2022-03-08 | Lovelace Biomedical Research Institute | Inhalable dry powder cytidine analogue composition and method of use as a treatment for cancer |
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